Bcl-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases

ABSTRACT

Disclosed are compounds which inhibit the activity of anti-apoptotic Bcl-2 or Bcl-xL proteins, compositions containing the compounds and methods of treating diseases during which are expressed anti-apoptotic Bcl-2 protein.

This application claims priority to U.S. Provisional Application Ser.No. 61/120,275 filed Dec. 5, 2008, and U.S. Provisional Application Ser.No. 61/181,180 filed May 26, 2009, which are incorporated by referencein their entirety.

FIELD OF THE INVENTION

This invention pertains to compounds which selectively inhibit theactivity of anti-apoptotic Bcl-2 family proteins, compositionscontaining the compounds, and methods of treating diseases during whichanti-apoptotic Bcl-2 proteins are expressed.

BACKGROUND OF THE INVENTION

Anti-apoptotic Bcl-2 family proteins are associated with a number ofdiseases and are under investigation as potential therapeutic drugtargets. These targets for interventional therapy include, for example,the Bcl-2 family proteins Bcl-2, Bcl-X_(L) and Bcl-w. Recently,inhibitors of Bcl-2 family proteins have been reported in commonly-ownedPCT/US/2004/36770, published as WO 2005/049593 and PCT/US/2004/367911,published as WO 2005/049594. While this art teaches inhibitors havinghigh binding to the target protein, compound binding affinity is onlyone of many parameters to be considered. One goal is to producecompounds that preferentially bind to, that is, are selective for, oneprotein over another protein. To exhibit this selectivity, it is wellknown that a compound not only displays a high binding affinity to aparticular protein but a lower binding affinity for another member aswell.

A typical measure of binding affinity of an anti-apoptotic proteininhibitor is the balance between the binding and dissociation processesbetween the protein and the inhibitor (K_(i)). The inhibition constant(K_(i)) is the dissociation constant of an enzyme-inhibitor complex or aprotein/small molecule complex, wherein the small molecule is inhibitingbinding of one protein to another protein. So a large K_(i) valueindicates a low binding affinity, and a small K_(i) value indicates ahigh binding affinity.

A typical measure of cellular activity of an anti-apoptotic proteininhibitor is the concentration eliciting 50% cellular effect (EC₅₀).

Accordingly, the inventors have discovered that while compounds taughtin the art have utility for the treatment of various cancers and immunediseases, they are not selective for anti-apoptotic Bcl-2 proteins overanti-apoptotic Bcl-X_(L) proteins and thereby result in a higherprobability of side effects characterized by inhibition ofanti-apoptotic Bcl-X_(L) proteins such as, thrombocytopenia.

This invention therefore comprises a series of compounds thatdemonstrate unexpected properties with respect to their selectivity forbinding to, and inhibiting the activity of anti-apoptotic Bcl-2 proteinover anti-apoptotic Bcl-X_(L) protein as significantly higher than thoseof the compounds taught in PCT/US/2004/36770 and PCT/US/2004/367911.

SUMMARY OF THE INVENTION

One embodiment of this invention, therefore, pertains to compounds ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,which are useful as selective inhibitors one or more than oneanti-apoptotic protein family member, the compounds having Formula (I)

wherein A¹ is N or C(A²);

one or two or three or each of A², B¹, D¹ and E¹ are independentlyselected R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ orN(CH₃)SO₂N(CH₃)R¹, and the remainder are independently selected H, F,Cl, Br, I, CN, CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); and

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂,C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷;

or

B¹ and Y¹, together with the atoms to which they are attached, areimidazole or triazole; and

one or two or each of A², D¹ and E¹ are independently selected R¹, OR¹,SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹,C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NHC(O)NHR¹, N(CH₃)C(O)N(CH₃)R¹,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ or N(CH₃)SO₂N(CH₃)R¹, and theremainder are independently selected H, F, Cl, Br, I, CF₃, C(O)OH,C(O)NH₂ or C(O)OR^(1A);

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is C₁-C₆-alkyl, C₃-C₆-alkenyl or C₃-C₆-alkynyl;

R² is phenyl which is unfused or fused with arene, heteroarene orR^(2A); R^(2A) is cycloalkane or heterocycloalkane;

R³ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(3A); R^(3A) is cycloalkane or heterocycloalkane;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with arene, heteroarene or R^(4A);R^(4A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶,NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷,SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃,CF₂CF₃, F, Cl, Br or I substituents;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(8A);

R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(9A); R^(9A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(10A); R^(10A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R¹², OR¹²,NHR¹², N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl which is unfused or fused with arene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, each of which is unfused or fused with arene,heteroarene or R^(14A) R^(14A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with arene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(18A); R^(18A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(19A); R^(19A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(20A); R^(20A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R²², OR²²,NHR²², N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R²² is R²³, R²⁴ or R²⁵;

R²³ is phenyl which is unfused or fused with arene, heteroarene orR^(23A); R^(23A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁴ is heteroarene which is unfused or fused with arene, heteroarene orR^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(25A); R^(25A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

Z¹ is R²⁶ or R²⁷, each of which is substituted with R²⁸, R²⁹ or R³⁰,each of which is substituted with F, Cl, Br, I, CH₂R³⁷, CH(R³¹)(R³⁷),C(R³¹)(R^(31A))(R³⁷), C(O)R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, NHR³⁷ orN(R³²)R³⁷;

R²⁶ is phenyl which is unfused or fused with arene or heteroarene;

R²⁷ is heteroarene which is unfused or fused with arene or heteroarene;

R²⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(28A); R^(28A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁹ is heteroaryl or R^(29A); R^(29A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁰ is cycloalkyl or cycloalkenyl, each having one or two CH₂ moietiesunreplaced or replaced with independently selected O, C(O), CNOH,CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N, and each of which is unfused or fused with arene,heteroarene or R^(30A); R^(30A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³¹ and R^(31A) are independently F, Cl, Br or alkyl or are takentogether and are C₂-C₅-spiroalkyl;

R³² is R³³, C(O)R³³ or C(O)OR³³;

R³³ is R³⁴ or R³⁵;

R³⁴ is phenyl which is unfused or fused with aryl, heteroaryl orR^(34A); R^(34A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁵ is alkyl which is unsubstituted or substituted with R³⁶;

R³⁶ is phenyl which is unfused or fused with arene, heteroarene orR^(36A); R^(36A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁷ is R³⁸, R³⁹ or R⁴⁰, each of which is substituted with F, Cl, Br, I,R⁴¹, OR⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹;

R³⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(38A); R^(38A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(39A); R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is C₃-C₈-cycloalkyl or C₄-C₈-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(40A); R^(40A) cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl which is unfused or fused with arene, heteroarene orR^(42A); R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴³ is heteroaryl which is unfused or fused with arene, heteroarene orR^(43A); R^(43A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁴ is C₃-C₉-cycloalkyl or C₄-C₇-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two independently selected R⁴⁶, OR⁴⁶, NHR⁴⁶,N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, OH, (O), C(O)OH, N₃, CN, NH₂,CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R⁴⁶ is R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁷ is phenyl which is unfused or fused with arene, heteroarene orR^(47A); R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁸ is heteroaryl or R^(48A); R^(48A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁹ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(49A); R^(49A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein the moieties represented by R²⁶ and R²⁷ are further substitutedby one or two or three of independently selected R^(50A), OR^(50A),SR^(50A), S(O)R^(50A), SO₂R^(50A) or NHR^(50A);

R^(50A) is R^(51A), R^(52A), R^(53A), R^(54A);

R⁵¹ is phenyl which is unfused or fused with benzene, heteroarene orR^(51AA),

wherein R^(51AA) is cycloalkane, cycloalkene or heterocycloalkaneheterocycloalkene,

R^(52A) is heteroaryl;

R^(53A) is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl; each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N, and each of which is unfused or fusedwith arene, heteroarene or R^(53AA);

wherein R^(53AA) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R^(54A) is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R⁵⁵,OR^(55AA), SR^(55AA), S(O)R^(55AA), SO₂R^(55AA), NHR^(55AA),N(R^(55AA))₂, C(O)R^(55AA), C(O)NH₂, C(O)NHR^(55AA), NHC(O)R^(55AA),NHSO₂R^(55AA), NHC(O)OR^(55AA), SO₂NH₂, SO₂NHR^(55AA), SO₂N(R^(55AA))₂,NHC(O)NH₂, NHC(O)NHR^(55AA), OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃,OCF₃, CF₂CF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R^(55AA) is alkyl, alkenyl, alkynyl, phenyl or heteroaryl, or R^(56A);

R^(56A) is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N;

wherein moieties represented by R² R³ R⁴, R⁶, R^(6C), R⁸, R^(8A), R⁹,R¹⁰, R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹ R²⁰, R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹,R³⁰, R³⁴, R³⁶, R³⁸, R³⁹, R⁴⁰, R⁴², R⁴³, R⁴⁴, R⁴⁷, R⁴⁸, and R⁴⁹ areindependently unsubstituted, further unsubstituted, substituted orfurther substituted with one or two or three or four or fiveindependently selected R⁵⁰, OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰,CO(O)R⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰, NH₂, NHR⁵⁰, N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰,C(O)N(R⁵⁰)₂, C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰, C(O)NR⁵⁵SO₂R⁵⁰, SO₂NH₂,SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰,C(N)N(R⁵⁰)₂, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Bror I substituents;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl which is unfused or fused with arene, heteroarene orR^(51B); R^(51B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵² is heteroaryl;

R⁵³ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(53B);

wherein R^(53B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁵⁵, OR⁵⁵,SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, NHR⁵⁵, N(R⁵⁵)₂, C(O)R⁵⁵, C(O)NH₂, C(O)NHR⁵⁵,NHC(O)R⁵⁵, NHSO₂R⁵⁵, NHC(O)OR⁵⁵, SO₂NH₂, SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂,NHC(O)NH₂, NHC(O)NHR⁵⁵, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃, OCF₃,CF₂CF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R⁵⁶;

wherein the alkyl, alkenyl, alkynyl are unsubstituted or substitutedwith OCH₃; and

R⁵⁶ is C₃-C₈-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N.

Another embodiment of this invention pertains to compounds ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,which are useful as selective inhibitors of anti-apoptotic Bcl-2proteins, the compounds having Formula (II)

wherein

R¹⁰⁰ is as described for substituents on R²⁶;

n is 0, 1, 2, or 3;

A¹ is N or C(A²);

one or two or three or each of A², B¹, D¹ and E¹ are independentlyselected R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NR¹C(O)NHR¹,NRC(O)N(R¹)₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ orN(CH₃)SO₂N(CH₃)R¹, and the remainder are independently selected H, F,Cl, Br, I, CN, CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); and

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂,C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷;

or

B¹ and Y¹, together with the atoms to which they are attached, areimidazole or triazole; and

one or two or each of A², D¹ and E¹ are independently selected R¹, OR¹,SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹,C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NHC(O)NHR¹, N(CH₃)C(O)N(CH₃)R¹,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ or N(CH₃)SO₂N(CH₃)R¹, and theremainder are independently selected H, F, Cl, Br, I, CF₃, C(O)OH,C(O)NH₂ or C(O)OR^(1A);

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is C₁-C₆-alkyl, C₃-C₆-alkenyl or C₃-C₆-alkynyl;

R² is phenyl which is unfused or fused with arene, heteroarene orR^(2A); R^(2A) is cycloalkane or heterocycloalkane;

R³ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(3A); R^(3A) is cycloalkane or heterocycloalkane;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with arene, heteroarene or R^(4A);R^(4A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶,NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷,SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃,CF₂CF₃, F, Cl, Br or I substituents;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(8A);

R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(9A); R^(9A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(10A); R^(10A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R¹², OR¹²,NHR¹², N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl which is unfused or fused with arene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, each of which is unfused or fused with arene,heteroarene or R^(14A); R^(14A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with arene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(18A); R^(18A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(19A); R^(19A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(20A); R^(20A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R²², OR²²,NHR²², N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R²² is R²³, R²⁴ or R²⁵;

R²³ is phenyl which is unfused or fused with arene, heteroarene orR^(23A); R^(23A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁴ is heteroarene which is unfused or fused with arene, heteroarene orR^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(25A); R^(25A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁰ is cycloalkyl or cycloalkenyl, each having one or two CH₂ moietiesunreplaced or replaced with independently selected O, C(O), CNOH,CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N, and each of which is unfused or fused with arene,heteroarene or R^(30A); R^(30A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; each of which is substitutedwith F, Cl, Br, I, CH₂R³⁷, CH(R³¹)(R³⁷), C(R³¹)(R^(31A))(R³⁷), C(O)R³⁷,OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, NHR³⁷ or N(R³²)R³⁷;

R³¹ and R^(31A) are independently F, Cl, Br or alkyl or are takentogether and are C₂-C₅-spiroalkyl;

R³² is R³³, C(O)R³³ or C(O)OR³³;

R³³ is R³⁴ or R³⁵;

R³⁴ is phenyl which is unfused or fused with aryl, heteroaryl orR^(34A); R^(34A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁵ is alkyl which is unsubstituted or substituted with R³⁶;

R³⁶ is phenyl which is unfused or fused with arene, heteroarene orR^(36A); R^(36A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁷ is R³⁸, R³⁹ or R⁴⁰, each of which is substituted with F, Cl, Br, I,R⁴¹, OR⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹;

R³⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(38A); R^(38A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(39A); R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is C₃-C₈-cycloalkyl or C₄-C₈-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(40A); R^(40A) cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl which is unfused or fused with arene, heteroarene orR^(42A); R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴³ is heteroaryl which is unfused or fused with arene, heteroarene orR^(43A); R^(43A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁴ is C₃-C₉-cycloalkyl or C₄-C₇-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two independently selected R⁴⁶, OR⁴⁶, NHR⁴⁶,N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, OH, (O), C(O)OH, N₃, CN, NH₂,CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R⁴⁶ is R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁷ is phenyl which is unfused or fused with arene, heteroarene orR^(47A); R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁸ is heteroaryl or R^(48A); R^(48A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁹ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(49A); R^(49A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein moieties represented by R² R³ R⁴, R⁶, R^(6C), R⁸, R^(8A) R⁹,R¹⁰R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰, R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰,R³⁴, R³⁶, R³⁸, R³⁹, R⁴⁰, R⁴², R⁴³, R⁴⁴, R⁴⁷, R⁴⁸, and R⁴⁹ areindependently unsubstituted, further unsubstituted, substituted orfurther substituted with one or two or three or four or fiveindependently selected R⁵⁰, OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰,CO(O)R⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰, NH₂, NHR⁵⁰, N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰,C(O)N(R⁵⁰)₂, C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰, C(O)NR⁵⁵SO₂R⁵⁰, SO₂NH₂,SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰,C(N)N(R⁵⁰)₂, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Bror I substituents;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl which is unfused or fused with arene, heteroarene orR^(51B); R^(51B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵² is heteroaryl;

R⁵³ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(53B);

wherein R^(53B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁵⁵, OR⁵⁵,SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, NHR⁵⁵, N(R⁵⁵)₂, C(O)R⁵⁵, C(O)NH₂, C(O)NHR⁵⁵,NHC(O)R⁵⁵, NHSO₂R⁵⁵, NHC(O)OR⁵⁵, SO₂NH₂, SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂,NHC(O)NH₂, NHC(O)NHR⁵⁵, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃, OCF₃,CF₂CF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R⁵⁶;

wherein the alkyl, alkenyl, alkynyl are unsubstituted or substitutedwith OCH₃; and

R⁵⁶ is C₃-C₈-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N.

Another embodiment of this invention pertains to compounds ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,which are useful as selective inhibitors of anti-apoptotic Bcl-2proteins, the compounds having Formula (III)

wherein

R¹⁰⁰ is as described for substituents on R²⁶;

n is 0, 1, 2, or 3;

A¹ is N or C(A²);

one or two or three or each of A², B¹, D¹ and E¹ are independentlyselected R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ orN(CH₃)SO₂N(CH₃)R¹, and the remainder are independently selected H, F,Cl, Br, I, CN, CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); and

-   -   Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃,        OCF₂CF₃, R¹⁷, OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷,        N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂, C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷        or NHSO₂R¹⁷;        or

B¹ and Y¹, together with the atoms to which they are attached, areimidazole or triazole; and

one or two or each of A², D¹ and E¹ are independently selected R¹, OR¹,SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹,C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NHC(O)NHR¹, N(CH₃)C(O)N(CH₃)R¹,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ or N(CH₃)SO₂N(CH₃)R¹, and theremainder are independently selected H, F, Cl, Br, I, CF₃, C(O)OH,C(O)NH₂ or C(O)OR^(1A); R¹ is R², R³, R⁴ or R⁵;

R^(1A) is C₁-C₆-alkyl, C₃-C₆-alkenyl or C₃-C₆-alkynyl;

R² is phenyl which is unfused or fused with arene, heteroarene orR^(2A); R^(2A) is cycloalkane or heterocycloalkane;

R³ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(3A); R^(3A) is cycloalkane or heterocycloalkane;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with arene, heteroarene or R^(4A);R^(4A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶,NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷,SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃,CF₂CF₃, F, Cl, Br or I substituents;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(8A);

R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(9A); R^(9A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(10A); R^(10A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R¹², OR¹²,NHR¹², N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl which is unfused or fused with arene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, each of which is unfused or fused with arene,heteroarene or R^(14A); R^(14A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with arene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(18A); R^(18A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(19A); R^(19A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(20A); R^(20A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R²², OR²²,NHR²², N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R²² is R²³, R²⁴ or R²⁵;

R²³ is phenyl which is unfused or fused with arene, heteroarene orR^(23A); R^(23A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁴ is heteroarene which is unfused or fused with arene, heteroarene orR^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(25A); R^(25A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁰ is cycloalkyl or cycloalkenyl, each having one or two CH₂ moietiesunreplaced or replaced with independently selected O, C(O), CNOH,CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N, and each of which is unfused or fused with arene,heteroarene or R^(30A); R^(30A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; each of which is substitutedwith F, Cl, Br, I, CH₂R³⁷, CH(R³¹)(R³⁷), C(R³¹)(R^(31A))(R³⁷), C(O)R³⁷,OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, NHR³⁷ or N(R³²)R³⁷;

R³¹ and R^(31A) are independently F, Cl, Br or alkyl or are takentogether and are C₂-C₅-spiroalkyl;

R³² is R³³, C(O)R³³ or C(O)OR³³;

R³³ is R³⁴ or R³⁵;

R³⁴ is phenyl which is unfused or fused with aryl, heteroaryl orR^(34A); R^(34A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁵ is alkyl which is unsubstituted or substituted with R³⁶;

R³⁶ is phenyl which is unfused or fused with arene, heteroarene orR^(36A); R^(36A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁷ is R³⁸, R³⁹ or R⁴⁰, each of which is substituted with F, Cl, Br, I,R⁴¹, OR⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹;

R³⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(38A); R^(38A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(39A); R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is C₃-C₈-cycloalkyl or C₄-C₈-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(40A); R^(40A) cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl which is unfused or fused with arene, heteroarene orR^(42A); R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴³ is heteroaryl which is unfused or fused with arene, heteroarene orR^(43A); R^(43A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁴ is C₃-C₉-cycloalkyl or C₄-C₇-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two independently selected R⁴⁶, OR⁴⁶, NHR⁴⁶,N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, OH, (O), C(O)OH, N₃, CN, NH₂,CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R⁴⁶ is R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁷ is phenyl which is unfused or fused with arene, heteroarene orR^(47A); R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁸ is heteroaryl or R^(48A); R^(48A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁹ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(49A); R^(49A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein moieties represented by R² R³ R⁴, R⁶, R^(6C), R⁸, R^(8A) R⁹,R¹⁰, R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰, R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹,R³⁰, R³⁴, R³⁶, R³⁸, R³⁹, R⁴⁰, R⁴², R⁴³, R⁴⁴, R⁴⁷, R⁴⁸, and R⁴⁹ areindependently unsubstituted, further unsubstituted, substituted orfurther substituted with one or two or three or four or fiveindependently selected R⁵⁰, OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰,CO(O)R⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰, NH₂, NHR⁵⁰, N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰,C(O)N(R⁵⁰)₂, C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰, C(O)NR⁵⁵SO₂R⁵⁰, SO₂NH₂,SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰,C(N)N(R⁵⁰)₂, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Bror I substituents;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl which is unfused or fused with arene, heteroarene orR^(51B); R^(51B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵² is heteroaryl;

R⁵³ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(53B);

wherein R^(53B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁵⁵, OR⁵⁵,SR⁵⁵, S(O)R⁵, SO₂R⁵⁵, NHR⁵⁵, N(R⁵⁵)₂, C(O)R⁵⁵, C(O)NH₂, C(O)NHR⁵⁵,NHC(O)R⁵⁵, NHSO₂R⁵⁵, NHC(O)OR⁵⁵, SO₂NH₂, SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂,NHC(O)NH₂, NHC(O)NHR⁵⁵, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃, OCF₃,CF₂CF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R⁵⁶;

wherein the alkyl, alkenyl, alkynyl are unsubstituted or substitutedwith OCH₃; and

R⁵⁶ is C₃-C₈-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N.

Another embodiment of this invention pertains to compounds ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,which are useful as selective inhibitors of anti-apoptotic Bcl-2proteins, the compounds having Formula (IV)

wherein

R¹⁰⁰ is as described for substituents on R²⁶;

n is 0, 1, 2, or 3;

A¹ is N or C(A²);

one or two or three or each of A², B¹, D¹ and E¹ are independentlyselected R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NR¹C(O)NHR¹,NRC(O)N(R¹)₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ orN(CH₃)SO₂N(CH₃)R¹, and the remainder are independently selected H, F,Cl, Br, I, CN, CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); and

Y is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂,C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷;

or

B¹ and Y¹, together with the atoms to which they are attached, areimidazole or triazole; and

one or two or each of A², D¹ and E¹ are independently selected R¹, OR¹,SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹,C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NHC(O)NHR¹, N(CH₃)C(O)N(CH₃)R¹,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ or N(CH₃)SO₂N(CH₃)R¹, and theremainder are independently selected H, F, Cl, Br, I, CF₃, C(O)OH,C(O)NH₂ or C(O)OR^(1A);

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is C₁-C₆-alkyl, C₃-C₆-alkenyl or C₃-C₆-alkynyl;

R² is phenyl which is unfused or fused with arene, heteroarene orR^(2A); R^(2A) is cycloalkane or heterocycloalkane;

R³ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(3A); R^(3A) is cycloalkane or heterocycloalkane;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with arene, heteroarene or R^(4A);R^(4A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶,NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷,SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃,CF₂CF₃, F, Cl, Br or I substituents;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(8A);

R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(9A); R^(9A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(10A); R^(10A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R¹², OR¹²,NHR¹², N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl which is unfused or fused with arene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, each of which is unfused or fused with arene,heteroarene or R^(14A) R^(14A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with arene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(18A); R^(18A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(19A); R^(19A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(20A); R^(20A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R²², OR²²,NHR²², N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R²² is R²³, R²⁴ or R²⁵;

R²³ is phenyl which is unfused or fused with arene, heteroarene orR^(23A); R^(23A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁴ is heteroarene which is unfused or fused with arene, heteroarene orR^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(25A); R^(25A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁰ is cycloalkyl or cycloalkenyl, each having one or two CH₂ moietiesunreplaced or replaced with independently selected O, C(O), CNOH,CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N, and each of which is unfused or fused with arene,heteroarene or R^(30A); R^(30A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; each of which is substitutedwith F, Cl, Br, I, CH₂R³⁷, CH(R³¹)(R³⁷), C(R³¹)(R^(31A))(R³⁷), C(O)R³⁷,OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, NHR³⁷ or N(R³²)R³⁷;

R³¹ and R^(31A) are independently F, Cl, Br or alkyl or are takentogether and are C₂-C₅-spiroalkyl;

R³² is R³³, C(O)R³³ or C(O)OR³³;

R³³ is R³⁴ or R³⁵;

R³⁴ is phenyl which is unfused or fused with aryl, heteroaryl orR^(34A); R^(34A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁵ is alkyl which is unsubstituted or substituted with R³⁶;

R³⁶ is phenyl which is unfused or fused with arene, heteroarene orR^(36A); R^(36A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁷ is R³⁸, R³⁹ or R⁴⁰, each of which is substituted with F, Cl, Br, I,R⁴¹, OR⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹;

R³⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(38A); R^(38A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(39A); R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is C₃-C₈-cycloalkyl or C₄-C₈-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(40A); R^(40A) cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl which is unfused or fused with arene, heteroarene orR^(42A); R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴³ is heteroaryl which is unfused or fused with arene, heteroarene orR^(43A); R^(43A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁴ is C₃-C₉-cycloalkyl or C₄-C₇-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two independently selected R⁴⁶, OR⁴⁶, NHR⁴⁶,N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, OH, (O), C(O)OH, N₃, CN, NH₂,CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R⁴⁶ is R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁷ is phenyl which is unfused or fused with arene, heteroarene orR^(47A); R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁸ is heteroaryl or R^(48A); R^(48A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁹ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(49A); R^(49A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein moieties represented by R² R³ R⁴, R⁶, R^(6C), R⁸, R^(8A) R⁹,R¹⁰, R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰, R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹,R³⁰, R³⁴, R³⁶, R³⁸, R³⁹, R⁴⁰, R⁴², R⁴³, R⁴⁴, R⁴⁷, R⁴⁸, and R⁴⁹ areindependently unsubstituted, further unsubstituted, substituted orfurther substituted with one or two or three or four or fiveindependently selected R⁵⁰, OR⁵, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰,CO(O)R⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰, NH₂, NHR⁵, N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰,C(O)N(R⁵⁰)₂, C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰, C(O)NR⁵⁵SO₂R⁵⁰, SO₂NH₂,SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰,C(N)N(R⁵⁰)₂, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Bror I substituents;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl which is unfused or fused with arene, heteroarene orR^(51B); R^(51B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵² is heteroaryl;

R⁵³ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(53B);

wherein R^(53B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁵⁵, OR⁵⁵,SR⁵⁵, S(O)R⁵⁵, SO₂R⁵, NHR⁵⁵, N(R⁵⁵)₂, C(O)R⁵⁵, C(O)NH₂, C(O)NHR⁵⁵,NHC(O)R⁵⁵, NHSO₂R⁵⁵, NHC(O)OR⁵⁵, SO₂NH₂, SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂,NHC(O)NH₂, NHC(O)NHR⁵⁵, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃, OCF₃,CF₂CF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R⁵⁶;

wherein the alkyl, alkenyl, alkynyl are unsubstituted or substitutedwith OCH₃; and

R⁵⁶ is C₃-C₈-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N.

Another embodiment of this invention pertains to compounds ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,which are useful as selective inhibitors of anti-apoptotic Bcl-2proteins, the compounds having Formula (V)

wherein

R¹⁰⁰ is as described for substituents on R²⁶;

n is 0, 1, 2, or 3;

A¹ is N or C(A²);

one or two or three or each of A², B¹, D¹ and E¹ are independentlyselected R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NR¹C(O)NHR¹,NRC(O)N(R¹)₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ orN(CH₃)SO₂N(CH₃)R¹, and the remainder are independently selected H, F,Cl, Br, I, CN, CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); and

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂,C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷;

or

B¹ and Y¹, together with the atoms to which they are attached, areimidazole or triazole; and

one or two or each of A², D¹ and E¹ are independently selected R¹, OR¹,SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹,C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NHC(O)NHR¹, N(CH₃)C(O)N(CH₃)R¹,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ or N(CH₃)SO₂N(CH₃)R¹, and theremainder are independently selected H, F, Cl, Br, I, CF₃, C(O)OH,C(O)NH₂ or C(O)OR^(1A);

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is C₁-C₆-alkyl, C₃-C₆-alkenyl or C₃-C₆-alkynyl;

R² is phenyl which is unfused or fused with arene, heteroarene orR^(2A); R^(2A) is cycloalkane or heterocycloalkane;

R³ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(3A); R^(3A) is cycloalkane or heterocycloalkane;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with arene, heteroarene or R^(4A);R^(4A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶,NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷,SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃,CF₂CF₃, F, Cl, Br or I substituents;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(8A);

R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(9A); R^(9A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(10A); R^(10A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R¹², OR¹²,NHR¹², N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl which is unfused or fused with arene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, each of which is unfused or fused with arene,heteroarene or R^(14A) R^(14A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with arene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(18A); R^(18A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(19A); R^(19A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(20A); R^(20A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R²², OR²²,NHR²², N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R²² is R²³, R²⁴ or R²⁵;

R²³ is phenyl which is unfused or fused with arene, heteroarene orR^(23A); R^(23A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁴ is heteroarene which is unfused or fused with arene, heteroarene orR^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(25A); R^(25A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁰ is cycloalkyl or cycloalkenyl, each having one or two CH₂ moietiesunreplaced or replaced with independently selected O, C(O), CNOH,CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N, and each of which is unfused or fused with arene,heteroarene or R^(30A); R^(30A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; each of which is substitutedwith F, Cl, Br, I, CH₂R³⁷, CH(R³¹)(R³⁷), C(R³¹)(R^(31A))(R³⁷), C(O)R³⁷,OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, NHR³⁷ or N(R³²)R³⁷;

R³¹ and R^(31A) are independently F, Cl, Br or alkyl or are takentogether and are C₂-C₅-spiroalkyl;

R³² is R³³, C(O)R³³ or C(O)OR³³;

R³³ is R³⁴ or R³⁵;

R³⁴ is phenyl which is unfused or fused with aryl, heteroaryl orR^(34A); R^(34A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁵ is alkyl which is unsubstituted or substituted with R³⁶;

R³⁶ is phenyl which is unfused or fused with arene, heteroarene orR^(36A); R^(36A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁷ is R³⁸, R³⁹ or R⁴⁰, each of which is substituted with F, Cl, Br, I,R⁴¹, OR⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹;

R³⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(38A); R^(38A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(39A); R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is C₃-C₈-cycloalkyl or C₄-C₈-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(40A); R^(40A) cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl which is unfused or fused with arene, heteroarene orR^(42A); R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴³ is heteroaryl which is unfused or fused with arene, heteroarene orR^(43A); R^(43A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁴ is C₃-C₉-cycloalkyl or C₄-C₇-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two independently selected R⁴⁶, OR⁴⁶, NHR⁴⁶,N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, OH, (O), C(O)OH, N₃, CN, NH₂,CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R⁴⁶ is R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁷ is phenyl which is unfused or fused with arene, heteroarene orR^(47A); R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁸ is heteroaryl or R^(48A); R^(48A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁹ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(49A); R^(49A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein moieties represented by R² R³ R⁴, R⁶, R^(6C), R⁸, R^(8A) R⁹,R¹⁰, R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰, R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹,R³⁰, R³⁴, R³⁶, R³⁸, R³⁹, R⁴⁰, R⁴², R⁴³, R⁴⁴, R⁴⁷, R⁴⁸, and R⁴⁹ areindependently unsubstituted, further unsubstituted, substituted orfurther substituted with one or two or three or four or fiveindependently selected R⁵⁰, OR⁵, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰,CO(O)R⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰, NH₂, NHR⁵⁰, N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰,C(O)N(R⁵⁰)₂, C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰, C(O)NR⁵⁵SO₂R⁵⁰, SO₂NH₂,SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰,C(N)N(R⁵⁰)₂, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Bror I substituents;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl which is unfused or fused with arene, heteroarene orR^(51B); R^(51B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵² is heteroaryl;

R⁵³ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(53B);

wherein R^(53B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁵⁵, OR⁵⁵,SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, NHR⁵⁵, N(R⁵⁵)₂, C(O)R⁵⁵, C(O)NH₂, C(O)NHR⁵⁵,NHC(O)R⁵⁵, NHSO₂R⁵⁵, NHC(O)OR⁵⁵, SO₂NH₂, SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂,NHC(O)NH₂, NHC(O)NHR⁵⁵, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃, OCF₃,CF₂CF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R⁵⁶;

wherein the alkyl, alkenyl, alkynyl are unsubstituted or substitutedwith OCH₃; and

R⁵⁶ is C₃-C₈-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N.

Another embodiment pertains to compounds of Formula (I), Formula (II),Formula (III), Formula (IV), or Formula (V) wherein A¹ is C(A²); and A²is H.

Another embodiment pertains to compounds of Formula (I), Formula (II),Formula (III), Formula (IV), or Formula (V) wherein A¹ is C(A²); A² isH; and B¹ is NHR¹.

Another embodiment pertains to compounds of Formula (I), Formula (II),Formula (III), Formula (IV), or Formula (V) wherein A¹ is C(A²); A² isH; B¹ is NHR¹; and D¹ is H.

Another embodiment pertains to compounds of Formula (I), Formula (II),Formula (III), Formula (IV), or Formula (V) wherein A¹ is C(A²); A² isH; B¹ is NHR¹; D¹ is H; and E¹ is H.

Another embodiment pertains to compounds of Formula (I), Formula (II),Formula (III), Formula (IV), or Formula (V) wherein A¹ is C(A²); A² isH; B¹ is NHR¹; D¹ is H; E¹ is H; and Y¹ is NO₂.

Still another embodiment pertains to compounds having Formula I whichare

-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(benzyloxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(2-phenylethoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenylthio)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenylthio)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(phenylthio)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenylsulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenylsulfinyl)benzamide;-   2-benzyl-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-benzyl-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-benzyl-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(2-phenylethyl)benzamide;-   2-(benzylamino)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-anilino-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-anilino-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-methoxy-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indazol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indazol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(1,2,3,4-tetrahydroquinolin-6-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-(1,2,3,4-tetrahydroquinolin-6-yloxy)benzamide;-   4-(4-((4′-chloro-4-(pyrrolidin-1-ylmethyl)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-cyclopentylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)-3-isobutylpiperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(2,4-dioxo-3-azabicyclo(3.2.0)hept-3-yl)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(3,3-dimethyl-2-oxoazetidin-1-yl)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(4-nitro-2H-1,2,3-triazol-2-yl)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((2-(2-piperidin-1-ylethoxy)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-((((1-ethylpyrrolidin-2-yl)methyl)amino)carbonyl)-4-methoxyphenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1-naphthyloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-naphthyloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-naphthyloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-naphthyloxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(quinolin-7-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(quinolin-6-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(isoquinolin-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(isoquinolin-5-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(quinolin-6-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-6-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(isoquinolin-7-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(isoquinolin-7-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-methoxyphenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-methylphenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   N-((3-((chloro(difluoro)methyl)sulfonyl)-4-((3-(dimethylamino)propyl)amino)phenyl)sulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   2-(1H-indol-4-yloxy)-4-(4-((2-(4-methoxyphenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4,4-dimethyl-2-(4-(trifluoromethyl)phenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4,4-dimethyl-2-(4-(trifluoromethoxy)phenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4,4-dimethyl-2-(3-(trifluoromethyl)phenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(3-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   N-((3-((chloro(difluoro)methyl)sulfonyl)-4-((1-methylpiperidin-4-yl)amino)phenyl)sulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenoxymethyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(pyridin-3-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(pyridin-3-yloxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(pyridin-4-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(pyridin-3-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(pyridin-4-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(4-methylpiperazin-1-yl)propyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)(methyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-cyano-4-((3-(dimethylamino)propyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-(trifluoromethyl)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(isopropyl(methyl)amino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(3-(dimethylamino)propoxy)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-(4-methylpiperazin-1-yl)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-(4-methylpiperazin-1-yl)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(3-(dimethylamino)propoxy)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(3-(dimethylamino)propoxy)-3-nitrophenyl)sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-(4-methylpiperazin-1-yl)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((4-(dimethylamino)-1-methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydro-1,4-benzodioxin-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-1,1′-biphenyl-2-carboxamide;-   5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-1,1′-biphenyl-2-carboxamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-4-(3-piperidin-1-ylpropoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-4-(3-(dimethylamino)propoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(3-piperidin-1-ylpropoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(3-(dimethylamino)propoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-3-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-3-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-4-(2-pyrrolidin-1-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-4-(2-(diisopropylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydro-1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclooct-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclooct-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((2-(dimethylamino)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((4-(dimethylamino)butyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((1-(phenylsulfonyl)piperidin-4-yl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((1-(quinolin-8-ylsulfonyl)piperidin-4-yl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((1-(phenylsulfonyl)piperidin-4-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((1-(quinolin-8-ylsulfonyl)piperidin-4-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(((1S)-3-(dimethylamino)-1-thien-2-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((thien-2-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((2-(1H-1,2,3-triazol-1-yl)ethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((2-(2H-1,2,3-triazol-2-yl)ethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-naphthyloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((2-(2-oxopyridin-1(2H)-yl)ethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((2-(pyridin-2-yloxy)ethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((2-pyridin-4-ylethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-(trifluoromethyl)phenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-cyano-4-((3-(dimethylamino)propyl)amino)phenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((4-methylpiperazin-1-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-(1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   N-((4-(((4-aminotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-3-fluoro-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-3-fluoro-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   N-[(4-{[(3S,4R)-1-benzyl-3-hydroxypiperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-[4-({4′-chloro-3-[3-(dimethylamino)propyl]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-{4-[(4′-chloro-4-morpholin-4-yl-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dimethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(dimethylamino)tetrahydro-2H-pyran-4-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   N-({4-[(2-aminocyclohexyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-[4-({4′-chloro-4-[3-(dimethylamino)prop-1-ynyl]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[1-(4,4,4-trifluorobutyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[2-(4-hydroxy-1-methylpiperidin-4-yl)ethyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-2-yl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[4′-chloro-4-(2-hydroxyethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(4,4,4-trifluorobutyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[4′-chloro-4-(2-hydroxyethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1-morpholin-4-ylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-2-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(2-hydroxyethyl)piperazin-1-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(3-fluoropropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-hydroxy-1-tetrahydro-2H-pyran-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-({1-[2-(1H-pyrazol-1-yl)ethyl]piperidin-4-yl}amino)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(methylamino)-3-nitrophenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(methylamino)-3-nitrophenyl]sulfonyl}benzamide;-   4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-morpholin-4-ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-[(4-{[(1-aminocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxopyrrolidin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-{4-[(1R)-1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-{4-[(1S)-1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-3-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(3-methyloxetan-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methoxycyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(1,1-dioxidothiomorpholin-4-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxopiperidin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxoimidazolidin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2-pyridin-4-ylethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-morpholin-4-yl-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(4-methoxypiperidin-1-yl)-3-nitrophenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-pyrrolidin-1-ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(3-oxopiperazin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-[4-({4′-chloro-4-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1,1-dioxidotetrahydrothien-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-(trifluoromethyl)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[2-(1,3-dioxolan-2-yl)ethyl]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[2-(3-oxopiperazin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methyl-5-oxopyrrolidin-3-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methyl-6-oxopiperidin-3-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(piperidin-1-ylamino)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(piperidin-1-ylamino)phenyl]sulfonyl}benzamide;-   4-(4-{[4-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methyloxetan-3-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(1-oxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1,3-thiazol-5-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2-tetrahydro-2H-pyran-4-ylethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[2-(trifluoromethoxy)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[3-(methylsulfonyl)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(1,1-dioxidothiomorpholin-4-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethyl)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(trifluoromethoxy)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2,2-difluoroethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4,4-difluorocyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethoxy)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[3-(methylsulfonyl)propoxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methoxypropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-methoxypropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(3R)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[Cis-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phenyl}sulfonyl)benzamide;-   N-({5-bromo-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1,1-dioxidotetrahydrothien-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-(methylamino)-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   N-{[5-bromo-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6-isopropoxypyridin-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[6-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(1,3-thiazol-2-yl)pyridin-3-yl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(2-methoxyethyl)amino]carbonyl}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[4′-chloro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[4′-chloro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide;-   4-{4-[(5-tert-butyl-4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-{4-[(5-tert-butyl-4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2S)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   N-({5-bromo-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)oxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-1-(3-hydroxypropyl)-1,2,5,6-tetrahydropyridin-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   benzyl    4-({[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenyl]amino}methyl)piperidine-1-carboxylate;-   N-{[3-(aminocarbonyl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[4′-chloro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-{4-[(5-tert-butyl-4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1-methyl-1H-imidazol-5-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylsulfonyl)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   N-{[5-bromo-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-5-(1,3-thiazol-2-yl)pyridin-3-yl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3,3-dimethylbutyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1S)-1-(hydroxymethyl)-3-methylbutyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R)-1-(hydroxymethyl)-2-methylpropyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methoxyphenyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   N-[(4-{[2-(1,3-benzodioxol-5-yl)ethyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-hydroxyphenyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   N-{[4-({2-[4-(aminosulfonyl)phenyl]ethyl}amino)-3-nitrophenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(1H-imidazol-1-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(1S)-1-phenylethyl]amino}phenyl)sulfonyl]benzamide;-   N-({2-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]thio}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]thio}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(methylsulfonyl)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(methylsulfonyl)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-hydroxy-4-methoxyphenyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-dihydro-1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(pyridin-3-ylamino)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(pyridin-3-ylamino)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(pyridin-3-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1,2,3,4-tetrahydroisoquinolin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide;-   N-[(5-chloro-6-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   Trans-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2,2-difluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   N-[(5-chloro-6-{[1-(cyanomethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydrofuran-3-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   Trans-N-({5-chloro-6-[(4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(cyanomethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-(2-methoxyethoxy)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(N,N-dimethylglycyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(cyanomethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-oxetan-3-ylmorpholin-2-yl)methyl]amino}phenyl)sulfonyl]benzamide;-   N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}oxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({(2R)-4-[2-(2-methoxyethoxy)ethyl]morpholin-2-yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   N-[(4-{[(4-acetylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methylsulfonyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-({4-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(2-tetrahydrofuran-2-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyanocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-tetrahydro-2H-pyran-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxy-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;-   N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxy-4-(4-{(3-phenylpropanoyl)    [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxy-4-(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;-   N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxy-4-(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;-   4-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)piperazin-1-yl]-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide;-   4-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;-   4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;-   4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide;-   4-(4-{2-[(4R,7S)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoinden-5-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;-   4-[4-(2-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;-   4-[4-(2-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzylidene)piperidin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;-   4-[4-(3-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;    and therapeutically acceptable salts, prodrugs, salts of prodrugs    and metabolites thereof.

Another embodiment pertains to a composition for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, chronic lymphocytic leukemia, myeloma, prostatecancer, small cell lung cancer or spleen cancer, said compositioncomprising an excipient and a therapeutically effective amount of thecompound of Formula (I).

Another embodiment pertains to a method of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said method comprisingadministering to the patient a therapeutically effective amount ofFormula (I).

Another embodiment pertains to a method of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said method comprisingadministering to the patient therapeutically effective amount of thecompound of Formula (I) and a therapeutically effective amount of oneadditional therapeutic agent or more than one additional therapeuticagent.

DETAILED DESCRIPTION OF THE INVENTION

Variable moieties herein are represented by identifiers (capital letterswith numerical and/or alphabetical superscripts) and may be specificallyembodied.

It is meant to be understood that proper valences are maintained for allmoieties and combinations thereof, that monovalent moieties having morethan one atom are drawn from left to right and are attached throughtheir left ends, and that divalent moieties are also drawn from left toright.

It is also meant to be understood that a specific embodiment of avariable moiety herein may be the same or different as another specificembodiment having the same identifier.

The term “alkenyl” as used herein, means a straight or branchedhydrocarbon chain containing from 2 to 10 carbons and containing atleast one carbon-carbon double bond. The term “C_(x)-C_(y) alkyl” meansa straight or branched hydrocarbon chain containing at least onecarbon-carbon double bond containing x to y carbon atoms. The term“C₃-C₆ alkenyl” means an alkenyl group containing 3-6 carbon atoms.Representative examples of alkenyl include, but are not limited to,buta-2,3-dienyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl,4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkenylene” means a divalent group derived from a straight orbranched chain hydrocarbon of 2 to 4 carbon atoms and contains at leastone carbon-carbon double bond. The term “C_(x)-C_(y) alkylene” means adivalent group derived from a straight or branched hydrocarbon chaincontaining at least one carbon-carbon double bond and containing x to ycarbon atoms. Representative examples of alkenylene include, but are notlimited to, —CH═CH— and —CH₂CH═CH—.

The term “alkyl” as used herein, means a straight or branched, saturatedhydrocarbon chain containing from 1 to 10 carbon atoms. The term“C_(X)-C_(y) alkyl” means a straight or branched chain, saturatedhydrocarbon containing x to y carbon atoms. For example “C₁-C₆ alkyl”means a straight or branched chain, saturated hydrocarbon containing 2to 6 carbon atoms. Representative examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl,n-octyl, n-nonyl, and n-decyl.

The term “alkylene” means a divalent group derived from a straight orbranched, saturated hydrocarbon chain of 1 to 10 carbon atoms, forexample, of 1 to 4 carbon atoms. The term “C_(X)-C_(y) alkylene” means adivalent group derived from a straight or branched chain, saturatedhydrocarbon containing x to y carbon atoms. For example “C₂-C₆ alkylene”means a straight or branched chain, saturated hydrocarbon containing 2to 6 carbon atoms. Representative examples of alkylene include, but arenot limited to, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and—CH₂CH(CH₃)CH₂—.

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. The term “C_(x)-C_(y) alkynyl”means a straight or branched chain hydrocarbon group containing from xto y carbon atoms. For example “C₃-C₆ alkynyl” means a straight orbranched chain hydrocarbon group containing from 3 to 6 carbon atoms andcontaining at least one carbon-carbon triple bond. Representativeexamples of alkynyl include, but are not limited to, acetylenyl,1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl.

The term “alkynylene,” as used herein, means a divalent radical derivedfrom a straight or branched chain hydrocarbon group containing from 2 to10 carbon atoms and containing at least one carbon-carbon triple bond.

The term “aryl” as used herein, means phenyl.

The term “cyclic moiety,” as used herein, means benzene, phenyl,phenylene, cycloalkane, cycloalkyl, cycloalkylene, cycloalkene,cycloalkenyl, cycloalkenylene, cycloalkyne, cycloalkynyl,cycloalkynylene, heteroarene, heteroaryl, heterocycloalkane,heterocycloalkyl, heterocycloalkene, heterocycloalkenyl and spiroalkyl.

The term “cycloalkylene” or cycloalkyl” or “cycloalkane” as used herein,means a monocyclic or bridged hydrocarbon ring system. The monocycliccycloalkyl is a carbocyclic ring system containing three to ten carbonatoms, zero heteroatoms and zero double bonds. Examples of monocyclicring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. The monocyclic ring may contain one or twoalkylene bridges, each consisting of one, two, or three carbon atoms,each linking two non-adjacent carbon atoms of the ring system.Representative examples of such bridged cycloalkyl ring systems include,but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.2.1]octane, bicyclo[3.2.2]nonane,bicyclo[3.3.1]nonane, bicyclo[4.2.1]nonane,tricyclo[3.3.1.0^(3,7)]nonane (octahydro-2,5-methanopentalene ornoradamantane), and tricyclo[3.3.1.1^(3,7)]decane (adamantane). Themonocyclic and bridged cycloalkyl can be attached to the parentmolecular moiety through any substitutable atom contained within thering system.

The term “cycloalkenylene,” or “cycloalkenyl” or “cycloalkene” as usedherein, means a monocyclic or a bridged hydrocarbon ring system. Themonocyclic cycloalkenyl has four to ten carbon atoms and zeroheteroatoms. The four-membered ring systems have one double bond, thefive- or six-membered ring systems have one or two double bonds, theseven- or eight-membered ring systems have one, two, or three doublebonds, and the nine- or ten-membered rings have one, two, three, or fourdouble bonds. Representative examples of monocyclic cycloalkenyl groupsinclude, but are not limited to, cyclobutenyl, cyclopentenyl,cyclohexenyl, cycloheptenyl, and cyclooctenyl. The monocycliccycloalkenyl ring may contain one or two alkylene bridges, eachconsisting of one, two, or three carbon atoms, each linking twonon-adjacent carbon atoms of the ring system. Representative examples ofthe bridged cycloalkenyl groups include, but are not limited to,bicyclo[2.2.1]hept-2-ene, 4,5,6,7-tetrahydro-3aH-indene,octahydronaphthalenyl, and 1,6-dihydro-pentalene. The monocyclic andbridged cycloalkenyl can be attached to the parent molecular moietythrough any substitutable atom contained within the ring systems.

The term “cycloalkyne,” or “cycloalkynyl,” or “cycloalkynylene,” as usedherein, means a monocyclic or a bridged hydrocarbon ring system. Themonocyclic cycloalkynyl has eight or more carbon atoms, zeroheteroatoms, and one or more triple bonds. The monocyclic cycloalkynylring may contain one or two alkylene bridges, each consisting of one,two, or three carbon atoms, each linking two non-adjacent carbon atomsof the ring system. The monocyclic and bridged cycloalkynyl can beattached to the parent molecular moiety through any substitutable atomcontained within the ring systems.

The term “heteroarene,” or “heteroaryl,” or “heteroarylene,” as usedherein, means a five-membered or six-membered aromatic ring having atleast one carbon atom and one or more than one independently selectednitrogen, oxygen or sulfur atom. The heteroarenes of this invention areconnected through any adjacent atoms in the ring, provided that propervalences are maintained. Representative examples of heteroaryl include,but are not limited to, furanyl (including, but not limited thereto,furan-2-yl), imidazolyl (including, but not limited thereto,1H-imidazol-1-yl), isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl,pyridinyl (e.g. pyridin-4-yl, pyridin-2-yl, pyridin-3-yl), pyridazinyl,pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl,1,3-thiazolyl, thienyl (including, but not limited thereto, thien-2-yl,thien-3-yl), triazolyl, and triazinyl.

The term “heterocycloalkane,” or “heterocycloalkyl,” or“heterocycloalkylene,” as used herein, means monocyclic or bridgedthree-, four-, five-, six-, seven-, or eight-membered ring containing atleast one heteroatom independently selected from the group consisting ofO, N, and S and zero double bonds. The monocyclic and bridgedheterocycloalkane are connected to the parent molecular moiety throughany substitutable carbon atom or any substitutable nitrogen atomcontained within the rings. The nitrogen and sulfur heteroatoms in theheterocycle rings may optionally be oxidized and the nitrogen atoms mayoptionally be quarternized. Representative examples of heterocycloalkanegroups include, but are not limited to, 8-azabicyclo[3.2.1]octane,3-azabicyclo[3.2.2]nonane, morpholinyl, tetrahydropyranyl, pyrrolidinyl,piperidinyl, dioxolanyl, tetrahydrofuranyl, thiomorpholinyl,1,4-dioxanyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxetanyl,piperazinyl, imidazolidinyl, azetidine, azepanyl, aziridinyl,diazepanyl, dithiolanyl, dithianyl, isoxazolidinyl, isothiazolidinyl,oxadiazolidinyl, oxazolidinyl, pyrazolidinyl, tetrahydrothienyl,thiadiazolidinyl, thiazolidinyl, thiomorpholinyl, trithianyl, andtrithianyl.

The term “heterocycloalkene,” or “heterocycloalkenyl,” or“heterocycloalkenylene,” as used herein, means monocyclic or bridgedthree-, four-, five-, six-, seven-, or eight-membered ring containing atleast one heteroatom independently selected from the group consisting ofO, N, and S and one or more double bonds. The monocyclic and bridgedheterocycloalkene are connected to the parent molecular moiety throughany substitutable carbon atom or any substitutable nitrogen atomcontained within the rings. The nitrogen and sulfur heteroatoms in theheterocycle rings may optionally be oxidized and the nitrogen atoms mayoptionally be quarternized. Representative examples of heterocycloalkenegroups include, but are not limited to, 1,4,5,6-tetrahydropyridazinyl,1,2,3,6-tetrahydropyridinyl, dihydropyranyl, imidazolinyl,isothiazolinyl, oxadiazolinyl, isoxazolinyl, oxazolinyl, pyranyl,pyrazolinyl, pyrrolinyl, thiadiazolinyl, thiazolinyl, and thiopyranyl.

The term “phenylene,” as used herein, means a divalent radical formed byremoval of a hydrogen atom from phenyl.

The term “spiroalkyl,” as used herein, means alkylene, both ends ofwhich are attached to the same carbon atom and is exemplified byC₂-spiroalkyl, C₃-spiroalkyl, C₄-spiroalkyl, C₅-spiroalkyl,C₆-spiroalkyl, C₇-spiroalkyl, C₈-spiroalkyl, C₉-spiroalkyl and the like.

The term “spiroheteroalkyl,” as used herein, means spiroalkyl having oneor two CH₂ moieties replaced with independently selected O, C(O), CNOH,CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N.

The term “spiroheteroalkenyl,” as used herein, means spiroalkenyl havingone or two CH₂ moieties replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N and also means spiroalkenyl having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties replacedwith N.

The term, “spirocyclo,” as used herein, means two substituents on thesame carbon atom, that, together with the carbon atom to which they areattached, form a cycloalkane, heterocycloalkane, cycloalkene, orheterocycloalkene ring.

The term “C₂-C₅-spiroalkyl,” as used herein, means C₂-spiroalkyl,C₃-spiroalkyl, C₄-spiroalkyl, and C₅-spiroalkyl.

The term “C₂-spiroalkyl,” as used herein, means eth-1,2-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “C₃-spiroalkyl,” as used herein, means prop-1,3-ylene, bothends of which replace hydrogen atoms of the same CH₂ moiety.

The term “C₄-spiroalkyl,” as used herein, means but-1,4-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “C₅-spiroalkyl,” as used herein, means pent-1,5-ylene, bothends of which replace hydrogen atoms of the same CH₂ moiety.

The term “C₆-spiroalkyl,” as used herein, means hex-1,6-ylene, both endsof which replace hydrogen atoms of the same CH₂ moiety.

The term “NH protecting group,” as used herein, meanstrichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl,para-nitrobenzylcarbonyl, ortho-bromobenzyloxycarbonyl, chloroacetyl,dichloroacetyl, trichloroacetyl, trifluoroacetyl, phenylacetyl, formyl,acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl,para-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyl-oxycarbonyl,4-(phenylazo)benzyloxycarbonyl, 2-furfuryl-oxycarbonyl,diphenylmethoxycarbonyl, 1,1-dimethylpropoxy-carbonyl,isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl,1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, diphenylmethyl,triphenylmethyl, 2-nitrophenylthio, methanesulfonyl,para-toluenesulfonyl, N,N-dimethylaminomethylene, benzylidene,2-hydroxybenzylidene, 2-hydroxy-5-chlorobenzylidene,2-hydroxy-1-naphthyl-methylene, 3-hydroxy-4-pyridylmethylene,cyclohexylidene, 2-ethoxycarbonylcyclohexylidene,2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene,3,3-dimethyl-5-oxycyclo-hexylidene, diphenylphosphoryl,dibenzylphosphoryl, 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl,trimethylsilyl, triethylsilyl, and triphenylsilyl.

The term “C(O)OH protecting group,” as used herein, means methyl, ethyl,n-propyl, isopropyl, 1,1-dimethylpropyl, n-butyl, tert-butyl, phenyl,naphthyl, benzyl, diphenylmethyl, triphenylmethyl, para-nitrobenzyl,para-methoxybenzyl, bis(para-methoxyphenyl)methyl, acetylmethyl,benzoylmethyl, para-nitrobenzoylmethyl, para-bromobenzoylmethyl,para-methanesulfonylbenzoylmethyl, 2-tetrahydropyranyl2-tetrahydrofuranyl, 2,2,2-trichloro-ethyl, 2-(trimethylsilyl)ethyl,acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl, phthalimidomethyl,succinimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,methoxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl)ethoxymethyl,benzyloxymethyl, methylthiomethyl, 2-methylthioethyl, phenylthiomethyl,1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl, trimethylsilyl,triethylsilyl, triisopropylsilyl, diethylisopropylsilyl,tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl,and tert-butylmethoxyphenylsilyl.

The term “OH or SH protecting group,” as used herein, meansbenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl,diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl,2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl,2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl,allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl,8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl,trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl,pivaloyl, benzoyl, methyl, tert-butyl, 2,2,2-trichloroethyl,2-trimethylsilylethyl, 1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl,allyl, benzyl(phenylmethyl), para-methoxybenzyl, 3,4-dimethoxybenzyl,diphenylmethyl, triphenylmethyl, tetrahydrofuryl, tetrahydropyranyl,tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, benzyloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloro-ethoxymethyl,2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, methanesulfonyl,para-toluenesulfonyl, trimethylsilyl, triethylsilyl, triisopropylsilyl,diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

Compounds

Geometric isomers may exist in the present compounds. Compounds of thisinvention may contain carbon-carbon double bonds or carbon-nitrogendouble bonds in the E or Z configuration, wherein the term “E”represents higher order substituents on opposite sides of thecarbon-carbon or carbon-nitrogen double bond and the term “Z” representshigher order substituents on the same side of the carbon-carbon orcarbon-nitrogen double bond as determined by the Cahn-Ingold-PrelogPriority Rules. The compounds of this invention may also exist as amixture of “E” and “Z” isomers. Substituents around a cycloalkyl orheterocycloalkyl are designated as being of cis or trans configuration.Furthermore, the invention contemplates the various isomers and mixturesthereof resulting from the disposal of substituents around an adamantanering system. Two substituents around a single ring within an adamantanering system are designated as being of Z or E relative configuration.For examples, see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. leNoble J. Org. Chem. 1998, 63, 2758-2760 and E. L. Eliel, and S. H.Wilen. (1994) Stereochemistry of Organic Compounds. New York, N.Y.: JohnWiley & Sons, Inc.

Compounds of this invention contain asymmetrically substituted carbonatoms in the R or S configuration, in which the terms “R” and “S” are asdefined by the IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem. (1976) 45, 13-10. Compounds havingasymmetrically substituted carbon atoms with equal amounts of R and Sconfigurations are racemic at those carbon atoms. Atoms with an excessof one configuration over the other are assigned the configurationpresent in the higher amount, preferably an excess of about 85%-90%,more preferably an excess of about 95%-99%, and still more preferably anexcess greater than about 99%. Accordingly, this invention includesracemic mixtures, relative and absolute stereoisomers, and mixtures ofrelative and absolute stereoisomers.

Compounds of this invention containing NH, C(O)OH, OH or SH moieties mayhave attached thereto prodrug-forming moieties. The prodrug-formingmoieties are removed by metabolic processes and release the compoundshaving the freed hydroxyl, amino or carboxylic acid in vivo. Prodrugsare useful for adjusting such pharmacokinetic properties of thecompounds as solubility and/or hydrophobicity, absorption in thegastrointestinal tract, bioavailability, tissue penetration, and rate ofclearance.

Isotope Enriched or Labeled Compounds

Compounds of the invention can exist in isotope-labeled or -enrichedform containing one or more atoms having an atomic mass or mass numberdifferent from the atomic mass or mass number most abundantly found innature. Isotopes can be radioactive or non-radioactive isotopes.Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur,fluorine, chlorine, and iodine include, but are not limited to, ²H, ³H,¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I. Compounds thatcontain other isotopes of these and/or other atoms are within the scopeof this invention.

In another embodiment, the isotope-labeled compounds contain deuterium(²H), tritium (³H) or ¹⁴C isotopes. Isotope-labeled compounds of thisinvention can be prepared by the general methods well known to personshaving ordinary skill in the art. Such isotope-labeled compounds can beconveniently prepared by carrying out the procedures disclosed in theExamples disclosed herein and Schemes by substituting a readilyavailable isotope-labeled reagent for a non-labeled reagent. In someinstances, compounds may be treated with isotope-labeled reagents toexchange a normal atom with its isotope, for example, hydrogen fordeuterium can be exchanged by the action of a deuteric acid such asD₂SO₄/D₂O. In addition to the above, relevant procedures andintermediates are disclosed, for instance, in Lizondo, J et al., DrugsFut, 21(11), 1116 (1996); Brickner, S J et al., J Med Chem, 39(3), 673(1996); Mallesham, B et al., Org Lett, 5(7), 963 (2003); PCTpublications WO1997010223, WO2005099353, WO1995007271, WO2006008754;U.S. Pat. Nos. 7,538,189; 7,534,814; 7,531,685; 7,528,131; 7,521,421;7,514,068; 7,511,013; and US Patent Application Publication Nos.20090137457; 20090131485; 20090131363; 20090118238; 20090111840;20090105338; 20090105307; 20090105147; 20090093422; 20090088416; and20090082471, the methods are hereby incorporated by reference.

The isotope-labeled compounds of the invention may be used as standardsto determine the effectiveness of Bcl-2 inhibitors in binding assays.Isotope containing compounds have been used in pharmaceutical researchto investigate the in vivo metabolic fate of the compounds by evaluationof the mechanism of action and metabolic pathway of thenonisotope-labeled parent compound (Blake et al. J. Pharm. Sci. 64, 3,367-391 (1975)). Such metabolic studies are important in the design ofsafe, effective therapeutic drugs, either because the in vivo activecompound administered to the patient or because the metabolites producedfrom the parent compound prove to be toxic or carcinogenic (Foster etal., Advances in Drug Research Vol. 14, pp. 2-36, Academic press,London, 1985; Kato et al., J. Labelled Comp. Radiopharmaceut.,36(10):927-932 (1995); Kushner et al., Can. J. Physiol. Pharmacol., 77,79-88 (1999).

In addition, non-radio active isotope containing drugs, such asdeuterated drugs called “heavy drugs,” can be used for the treatment ofdiseases and conditions related to Bcl-2 activity. Increasing the amountof an isotope present in a compound above its natural abundance iscalled enrichment. Examples of the amount of enrichment include fromabout 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, 21, 25, 29, 33, 37,42, 46, 50, 54, 58, 63, 67, 71, 75, 79, 84, 88, 92, 96, to about 100 mol%. Replacement of up to about 15% of normal atom with a heavy isotopehas been effected and maintained for a period of days to weeks inmammals, including rodents and dogs, with minimal observed adverseeffects (Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770;Thomson J F, Ann. New York Acad. Sci 1960 84: 736; Czakja D M et al.,Am. J. Physiol. 1961 201: 357). Acute replacement of as high as 15%-23%in human fluids with deuterium was found not to cause toxicity(Blagojevic N et al. in “Dosimetry & Treatment Planning for NeutronCapture Therapy”, Zamenhof R, Solares G and Harling O Eds. 1994.Advanced Medical Publishing, Madison Wis. pp. 125-134; Diabetes Metab.23: 251 (1997)).

Stable isotope labeling of a drug can alter its physico-chemicalproperties such as pKa and lipid solubility. These effects andalterations can affect the pharmacodynamic response of the drug moleculeif the isotopic substitution affects a region involved in aligand-receptor interaction. While some of the physical properties of astable isotope-labeled molecule are different from those of theunlabeled one, the chemical and biological properties are the same, withone important exception: because of the increased mass of the heavyisotope, any bond involving the heavy isotope and another atom will bestronger than the same bond between the light isotope and that atom.Accordingly, the incorporation of an isotope at a site of metabolism orenzymatic transformation will slow said reactions potentially alteringthe pharmcokinetic profile or efficacy relative to the non-isotopiccompound.

Amides, Esters and Prodrugs

Prodrugs are derivatives of an active drug designed to ameliorate someidentified, undesirable physical or biological property. The physicalproperties are usually solubility (too much or not enough lipid oraqueous solubility) or stability related, while problematic biologicalproperties include too rapid metabolism or poor bioavailability whichitself may be related to a physicochemical property.

Prodrugs are usually prepared by: a) formation of ester, hemi esters,carbonate esters, nitrate esters, amides, hydroxamic acids, carbamates,imines, Mannich bases, phosphates, phosphate esters, and enamines of theactive drug, b) functionalizing the drug with azo, glycoside, peptide,and ether functional groups, c) use of aminals, hemi-aminals, polymers,salts, complexes, phosphoramides, acetals, hemiacetals, and ketal formsof the drug. For example, see Andrejus Korolkovas's, “Essentials ofMedicinal Chemistry”, John Wiley-Interscience Publications, John Wileyand Sons, New York (1988), pp. 97-118, which is incorporated in itsentirety by reference herein.

Esters can be prepared from substrates of formula (I) containing eithera hydroxyl group or a carboxy group by general methods known to personsskilled in the art. The typical reactions of these compounds aresubstitutions replacing one of the heteroatoms by another atom, forexample:

Amides can be prepared from substrates of formula (I) containing eitheran amino group or a carboxy group in similar fashion. Esters can alsoreact with amines or ammonia to form amides.

Another way to make amides from compounds of formula (I) is to heatcarboxylic acids and amines together.

In Schemes 2 and 3 above, R and R′ are independently substrates offormula (I), alkyl or hydrogen.

Suitable groups for A¹, B¹, D¹, E¹, Y¹, and Z¹ in compounds of Formula(I) are independently selected. The described embodiments of the presentinvention may be combined. Such combination is contemplated and withinthe scope of the present invention. For example, it is contemplated thatembodiments for any of A¹, B¹, D¹, E¹, Y¹, and Z¹ can be combined withembodiments defined for any other of A¹, B¹, D¹, E¹, Y¹, and Z¹.

One embodiment of this invention, therefore, pertains to compounds ortherapeutically acceptable salts, prodrugs or salts of prodrugs thereof,which are useful as selective inhibitors one or more than oneanti-apoptotic protein family member, the compounds having formula (I)

wherein A¹ is N or C(A²);

one or two or three or each of A², B¹, D¹ and E¹ are independentlyselected R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ orN(CH₃)SO₂N(CH₃)R¹, and the remainder are independently selected H, F,Cl, Br, I, CN, CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); and

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂,C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷;

or

B¹ and Y¹, together with the atoms to which they are attached, areimidazole or triazole; and

one or two or each of A², D¹ and E¹ are independently selected R¹, OR¹,SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹,C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NHC(O)NHR¹, N(CH₃)C(O)N(CH₃)R¹,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ or N(CH₃)SO₂N(CH₃)R¹, and theremainder are independently selected H, F, Cl, Br, I, CF₃, C(O)OH,C(O)NH₂ or C(O)OR^(1A);

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is C₁-C₆-alkyl, C₃-C₆-alkenyl or C₃-C₆-alkynyl;

R² is phenyl which is unfused or fused with arene, heteroarene orR^(2A); R^(2A) is cycloalkane or heterocycloalkane;

R³ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(3A); R^(3A) is cycloalkane or heterocycloalkane;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with arene, heteroarene or R^(4A);R^(4A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶,NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷,SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃,CF₂CF₃, F, Cl, Br or I substituents;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(8A);

R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(9A); R^(9A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(10A); R^(10A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R¹², OR¹²,NHR¹², N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl which is unfused or fused with arene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, each of which is unfused or fused with arene,heteroarene or R^(14A); R^(14A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with arene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(18A); R^(18A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(19A); R^(19A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(20A); R^(20A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R²², OR²²,NHR²², N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R²² is R²³, R²⁴ or R²⁵;

R²³ is phenyl which is unfused or fused with arene, heteroarene orR^(23A); R^(23A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁴ is heteroarene which is unfused or fused with arene, heteroarene orR^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(25A); R^(25A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

Z¹ is R²⁶ or R²⁷, each of which is substituted with R²⁸, R²⁹ or R³⁰,each of which is substituted with F, Cl, Br, I, CH₂R³⁷, CH(R³¹)(R³⁷),C(R³¹)(R^(31A))(R³⁷), C(O)R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, NHR³⁷ orN(R³²)R³⁷;

R²⁶ is phenyl which is unfused or fused with arene or heteroarene;

R²⁷ is heteroarene which is unfused or fused with arene or heteroarene;

R²⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(28A); R^(28A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene

R²⁹ is heteroaryl or R^(29A); R^(29A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁰ is cycloalkyl or cycloalkenyl, each having one or two CH₂ moietiesunreplaced or replaced with independently selected O, C(O), CNOH,CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N, and each of which is unfused or fused with arene,heteroarene or R^(30A); R^(30A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³¹ and R^(31A) are independently F, Cl, Br or alkyl or are takentogether and are C₂-C₅-spiroalkyl;

R³² is R³³, C(O)R³³ or C(O)OR³³;

R³³ is R³⁴ or R³⁵;

R³⁴ is phenyl which is unfused or fused with aryl, heteroaryl orR^(34A); R^(34A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁵ is alkyl which is unsubstituted or substituted with R³⁶;

R³⁶ is phenyl which is unfused or fused with arene, heteroarene orR^(36A); R^(36A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁷ is R³⁸, R³⁹ or R⁴⁰, each of which is substituted with F, Cl, Br, I,R⁴¹, OR⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹;

R³⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(38A); R^(38A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(39A); R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is C₃-C₈-cycloalkyl or C₄-C₈-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(40A); R^(40A) cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl which is unfused or fused with arene, heteroarene orR^(42A); R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴³ is heteroaryl which is unfused or fused with arene, heteroarene orR^(43A); R^(43A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁴ is C₃-C₉-cycloalkyl or C₄-C₇-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two independently selected R⁴⁶, OR⁴⁶, NHR⁴⁶,N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, OH, (O), C(O)OH, N₃, CN, NH₂,CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R⁴⁶ is R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁷ is phenyl which is unfused or fused with arene, heteroarene orR^(47A); R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁸ is heteroaryl or R^(48A); R^(48A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁹ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(49A); R^(49A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein the moieties represented by R²⁶ and R²⁷ are further substitutedby one or two or three of independently selected R^(50A), OR^(50A),SR^(50A), S(O)R^(50A), SO₂R⁵⁰ or NHR^(50A),

R^(50A) is R^(51A), R^(52A), R^(53A) or R^(54A);

R^(51A) is phenyl which is unfused or fused with benzene, heteroarene orR^(51AA),

wherein R^(51AA) is cycloalkane, cycloalkene or heterocycloalkaneheterocycloalkene,

R^(52A) is heteroaryl;

R^(53A) is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl; each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N, and each of which is unfused or fusedwith arene, heteroarene or R^(53AA);

wherein R^(53AA) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R^(54A) is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three of independently selected R^(55AA),OR^(55AA), SR^(55AA), S(O)R^(55AA), SO₂R^(55AA), NHR^(55AA),N(R^(55AA))₂, C(O)R^(55AA), C(O)NH₂, C(O)NHR^(55AA), NHC(O)R^(55AA),NHSO₂R^(55AA), NHC(O)OR^(55AA), SO₂NH₂, SO₂NHR^(55AA), SO₂N(R^(55AA))₂,NHC(O)NH₂, NHC(O)NHR^(55AA), OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃,OCF₃, CF₂CF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R^(55AA) is alkyl, alkenyl, alkynyl, phenyl or heteroaryl, or R^(56A);

R^(56A) is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N;

wherein moieties represented by R² R³ R⁴, R⁶, R^(6C), R⁸, R^(8A) R⁹,R¹⁰, R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰, R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹,R³⁰, R³⁴, R³⁶, R³⁸, R³⁹, R⁴⁰, R⁴², R⁴³, R⁴⁴, R⁴⁷, R⁴⁸, and R⁴⁹ areindependently unsubstituted, further unsubstituted, substituted orfurther substituted with one or two or three or four or fiveindependently selected R⁵⁰, OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰,CO(O)R⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰, NH₂, NHR⁵⁰, N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰,C(O)N(R⁵⁰)₂, C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰, C(O)NR⁵⁵SO₂R⁵⁰, SO₂NH₂,SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰,C(N)N(R⁵⁰)₂, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Bror I substituents;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl which is unfused or fused with arene, heteroarene orR^(51B); R^(51B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵² is heteroaryl;

R⁵³ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(53B);

wherein R^(53B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁵⁵, OR⁵⁵,SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, NHR⁵⁵, N(R⁵⁵)₂, C(O)R⁵⁵, C(O)NH₂, C(O)NHR⁵⁵,NHC(O)R⁵⁵, NHSO₂R⁵⁵, NHC(O)OR⁵⁵, SO₂NH₂, SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂,NHC(O)NH₂, NHC(O)NHR⁵⁵, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃, OCF₃,CF₂CF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R⁵⁶; and

wherein the alkyl, alkenyl, alkynyl are unsubstituted or substitutedwith OCH₃; and

R⁵⁶ is C₃-C₈-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N.

Another embodiment of this invention pertains to compounds of Formula(I), wherein A¹ is N or C(A²);

one or two or three or each of A², B¹, D¹ and E¹ are independentlyselected R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹,N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NR¹C(O)NHR¹,NR¹C(O)N(R¹)₂, SO₂NHR¹, SO₂N(R)₂, NHSO₂R¹, NHSO₂NHR¹ orN(CH₃)SO₂N(CH₃)R¹, and the remainder are independently selected H, F,Cl, Br, I, CN, CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); and

Y¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂,C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷;

or

B¹ and Y¹, together with the atoms to which they are attached, areimidazole or triazole; and

one or two or each of A², D¹ and E¹ are independently selected R¹, OR¹,SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹,C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NHC(O)NHR¹, N(CH₃)C(O)N(CH₃)R¹,SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ or N(CH₃)SO₂N(CH₃)R¹, and theremainder are independently selected H, F, Cl, Br, I, CF₃, C(O)OH,C(O)NH₂ or C(O)OR^(1A);

R¹ is R², R³, R⁴ or R⁵;

R^(1A) is C₁-C₆-alkyl, C₃-C₆-alkenyl or C₃-C₆-alkynyl;

R² is phenyl which is unfused or fused with arene, heteroarene orR^(2A); R^(2A) is cycloalkane or heterocycloalkane;

R³ is heteroaryl which is unfused or fused with benzene, heteroarene orR^(3A); R^(3A) is cycloalkane or heterocycloalkane;

R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl,each of which is unfused or fused with arene, heteroarene or R^(4A);R^(4A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁶,NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷, SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷,C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷, NHSO₂R⁷, NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷,SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃,CF₂CF₃, F, Cl, Br or I substituents;

R⁶ is C₂-C₅-spiroalkyl, each of which is unsubstituted or substitutedwith OH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) orN(CH₃)₂;

R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C);

R^(6C) is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl orpiperidin-1-yl, each having one CH₂ moiety unreplaced or replaced withO, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl which is unfused or fused with arene, heteroarene or R^(A);

R^(8A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(9A); R^(9A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(10A); R^(10A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R¹², OR¹²,NHR¹², N(R¹²)₂, C(O)NH₂, C(O)NHR¹², C(O)N(R¹²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶;

R¹³ is phenyl which is unfused or fused with arene, heteroarene orR^(13A); R^(13A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁴ is heteroaryl, each of which is unfused or fused with arene,heteroarene or R^(14A) R^(14A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene,each of which is unfused or fused with arene, heteroarene or R^(15A);R^(15A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁶ is alkyl, alkenyl or alkynyl;

R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹;

R¹⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(18A); R^(18A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R¹⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(19A); R^(19A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁰ is C₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(20A); R^(20A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R²¹ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R²², OR²²,NHR²², N(R²²)₂, C(O)NH₂, C(O)NHR²², C(O)N(R²²)₂, OH, (O), C(O)OH, N₃,CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R²² is R²³, R²⁴ or R²⁵;

R²³ is phenyl which is unfused or fused with arene, heteroarene orR^(23A); R^(23A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁴ is heteroarene which is unfused or fused with arene, heteroarene orR^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²⁵ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(25A); R^(25A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

Z¹ is R²⁶ or R²⁷, each of which is substituted with R²⁸, R²⁹ or R³⁰,each of which is substituted with F, Cl, Br, I, CH₂R³⁷, CH(R³¹)(R³⁷),C(R³¹)(R^(31A))(R³⁷), C(O)R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, NHR³⁷ orN(R³²)R³⁷;

R²⁶ is phenyl which is unfused or fused with arene or heteroarene;

R²⁷ is heteroarene which is unfused or fused with arene or heteroarene;

R²⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(28A); R^(28A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene

R²⁹ is heteroaryl or R^(29A); R^(29A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³⁰ is cycloalkyl or cycloalkenyl, each having one or two CH₂ moietiesunreplaced or replaced with independently selected O, C(O), CNOH,CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplaced orreplaced with N, and each of which is unfused or fused with arene,heteroarene or R^(30A); R^(30A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R³¹ and R^(31A) are independently F, Cl, Br or alkyl or are takentogether and are C₂-C₅-spiroalkyl;

R³² is R³³, C(O)R³³ or C(O)OR³³;

R³³ is R³⁴ or R³⁵;

R³⁴ is phenyl which is unfused or fused with aryl, heteroaryl orR^(34A); R^(34A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁵ is alkyl which is unsubstituted or substituted with R³⁶;

R³⁶ is phenyl which is unfused or fused with arene, heteroarene orR^(36A); R^(36A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁷ is R³⁸, R³⁹ or R⁴⁰, each of which is substituted with F, Cl, Br, I,R⁴¹, OR⁴¹, NHR⁴¹, N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹;

R³⁸ is phenyl which is unfused or fused with arene, heteroarene orR^(38A); R^(38A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R³⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(39A); R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁰ is C₃-C₈-cycloalkyl or C₄-C₈-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(40A); R^(40A) cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵;

R⁴² is phenyl which is unfused or fused with arene, heteroarene orR^(42A); R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴³ is heteroaryl which is unfused or fused with arene, heteroarene orR^(43A); R^(43A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁴ is C₃-C₉-cycloalkyl or C₄-C₇-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁵ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two independently selected R⁴⁶, OR⁴⁶, NHR⁴⁶,N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, OH, (O), C(O)OH, N₃, CN, NH₂,CF₃, CF₂CF₃, F, Cl, Br or I substituents;

R⁴⁶ is R⁴⁷, R⁴⁸ or R⁴⁹;

R⁴⁷ is phenyl which is unfused or fused with arene, heteroarene orR^(47A); R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁴⁸ is heteroaryl or R^(48A); R^(48A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

R⁴⁹ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(49A); R^(49A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene;

wherein the moieties represented by R²⁶ and R²⁷ are further substitutedwith OR^(50A);

R^(50A) is R^(51A);

R^(51A) is phenyl which is fused with heteroarene;

wherein moieties represented by R² R³ R⁴, R⁶, R^(6C), R⁸, R^(8A) R⁹,R¹⁰, R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰, R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹,R³⁰, R³⁴, R³⁶, R³⁸, R³⁹, R⁴⁰, R⁴², R⁴³, R⁴⁴, R⁴⁷, R⁴⁸, and R⁴⁹ areindependently unsubstituted, further unsubstituted, substituted orfurther substituted with one or two or three or four or fiveindependently selected R⁵⁰, OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰,CO(O)R⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰, NH₂, NHR⁵⁰, N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰,C(O)N(R⁵⁰)₂, C(O)NHOH, C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰, C(O)NR⁵⁵SO₂R⁵⁰, SO₂NH₂,SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂, CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰,C(N)N(R⁵⁰)₂, OH, (O), CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Bror I substituents;

R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴;

R⁵¹ is phenyl which is unfused or fused with arene, heteroarene orR^(51B); R^(51B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵² is heteroaryl;

R⁵³ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(53B);

wherein R^(53B) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R⁵⁴ is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two or three independently selected R⁵⁵, OR⁵⁵,SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, NHR⁵⁵, N(R⁵⁵)₂, C(O)R⁵⁵, C(O)NH₂, C(O)NHR⁵⁵,NHC(O)R⁵⁵, NHSO₂R⁵⁵, NHC(O)OR⁵⁵, SO₂NH₂, SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂,NHC(O)NH₂, NHC(O)NHR⁵⁵, OH, (O), C(O)OH, (O), N₃, CN, NH₂, CF₃, OCF₃,CF₂CF₃, OCF₂CF₃, F, Cl, Br or I substituents;

R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R⁵⁶; and

wherein the alkyl, alkenyl, alkynyl are unsubstituted or substitutedwith OCH₃; and

R⁵⁶ is C₃-C₈-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N.

In one embodiment of Formula (I), A¹ is N or C(A²);

one or two or three or each of A², B¹, D¹ and E¹ are independentlyselected R¹, OR¹, SR¹, SO₂R¹, NHR¹, N(R¹)₂, or C(O)NHR¹, and theremainder are independently selected H, F, Cl, Br, or I;

Y¹ is H, CN, NO₂, F, Cl, Br, I, CF₃, R¹⁷, NHC(O)R¹⁷, or C(O)NH₂;

R¹ is R², R³, R⁴ or R⁵;

R² is phenyl;

R³ is heteroaryl;

R⁴ is cycloalkyl, heterocycloalkyl or heterocycloalkenyl, each of whichis unfused or fused with R^(4A); R^(4A) is cycloalkane;

R⁵ is alkyl, or alkynyl, each of which is unsubstituted or substitutedwith one or two or three independently selected R⁶, R⁷, OR⁷, SR⁷, SO₂R⁷,N(R⁷)₂, OH, CN, CF₃, F, Cl, Br or I substituents;

R⁶ is C₂-C₅-spiroalkyl;

R⁷ is R⁸, R⁹, R¹⁰ or R¹¹;

R⁸ is phenyl which is unfused or fused with R^(8A);

R^(8A) is heterocycloalkane;

R⁹ is heteroaryl;

R¹⁰ is C₃-C₁₀-cycloalkyl, each having one or two CH₂ moieties unreplacedor replaced with independently selected O, S(O), SO₂ or NH and one ortwo CH moieties unreplaced or replaced with N;

R¹¹ is alkyl, each of which is unsubstituted or substituted with one ortwo or three independently selected OR¹², F, Cl, Br or I substituents;

R¹² is R¹⁶;

R¹⁶ is alkyl;

R¹⁷ is R¹⁹ or R²¹;

R¹⁹ is heteroaryl which is unfused or fused with arene, heteroarene orR^(19A); R^(19A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene;

R²¹ is alkynyl;

Z¹ is R²⁶, each of which is substituted with R³⁰, each of which issubstituted with F, Cl, Br, I, CH₂R³⁷, or CH(R³¹)(R³⁷);

R²⁶ is phenyl;

R³⁰ is cycloalkyl, each having two CH₂ moieties unreplaced or replacedwith NH;

R³¹ and R^(31A) are independently alkyl;

R³⁷ is R³⁸, R³⁹ or R⁴⁰, each of which is substituted with F, Cl, Br, I,NHR⁴¹, or R⁴¹;

R³⁸ is phenyl;

R³⁹ is heteroaryl;

R⁴⁰ is C₃-C₈-cycloalkyl or C₄-C₈-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH;

R⁴¹ is R⁴², R⁴³, or R⁴⁴;

R⁴² is phenyl;

R⁴³ is heteroaryl;

R⁴⁴ is C₃-C₉-cycloalkyl or C₄-C₇-cycloalkenyl, each having one or twoCH₂ moieties unreplaced or replaced with independently selected NH andone or two CH moieties unreplaced or replaced with N, and each of whichis unfused or fused with R^(44A); R^(44A) is cycloalkane;

wherein the moiety represented by R²⁶ is further substituted by one ortwo or three of independently selected R^(50A), OR^(50A), SR^(50A),S(O)R^(50A), SO₂R^(50A) or NHR^(50A);

R^(50A) is R^(51A), R^(52A) or R^(54A);

R^(51A) is phenyl which is unfused or fused with benzene, heteroarene orR^(51AA);

wherein R^(51AA) is heterocycloalkane;

R^(52A) is heteroaryl;

R^(54A) is alkyl, each of which is unsubstituted or substituted with oneor two or three of independently selected R^(55AA), or OR^(55AA);

R^(55AA) is phenyl;

wherein moieties represented by R² R³ R⁴, R⁶, R^(6C), R⁸, R^(8A) R⁹,R¹⁰, R¹³, R¹⁴, R¹⁵, R¹⁸, R¹⁹, R²⁰, R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹,R³⁰, R³⁴, R³⁶, R³⁸, R³⁹, R⁴⁰, R⁴², R⁴³, R⁴⁴, R⁴⁷, R⁴⁸, and R⁴⁹ areindependently unsubstituted, further unsubstituted, substituted orfurther substituted with one or two or three or four or fiveindependently selected R⁵⁰, OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰,CO(O)R⁵⁰, NH₂, NHR⁵⁰, SO₂NH₂, OH, (O), CN, CF₃, OCF₃, F, Cl, Br or Isubstituents;

R⁵⁰ is R⁵¹, R⁵², or R⁵⁴;

R⁵¹ is phenyl which is unfused or fused with arene, heteroarene orR^(51B); R^(51B) is heterocycloalkane;

R⁵² is heteroaryl;

R⁵³ is C₃-C₆-cycloalkyl, each having one or two CH₂ moieties unreplacedor replaced with independently selected O, and one or two CH moietiesunreplaced or replaced with N;

R⁵⁴ is alkyl, each of which is unsubstituted or substituted with one ortwo or three independently selected R⁵⁵, OR⁵⁵, N(R⁵⁵)₂, OH, CN, F, Cl,Br or I substituents; and

R⁵⁵ is alkyl or phenyl;

wherein the alkyl is unsubstituted or substituted with OCH₃; and

R⁵⁶ is C₃-C₈-cycloalkyl, each having one or two CH₂ moieties unreplacedor replaced with independently selected NH and one or two CH moietiesunreplaced or replaced with N.

In one embodiment of Formula (I), A¹ is N. In another embodiment ofFormula (I), A¹ is C(A²). In another embodiment of Formula (I), A¹ isC(A²), and A² is H.

In one embodiment of Formula (I), B¹ is R¹, OR¹, SR¹, SO₂R¹, NHR¹,N(R¹)₂, or C(O)NHR¹. In another embodiment of Formula (I), B¹ is NHR¹.In another embodiment of Formula (I), B¹ is NHR¹, and A¹ is C(A²), andA² is H. In another embodiment of Formula (I), B¹ is OR¹. In anotherembodiment of Formula (I), B¹ is OR¹, and A¹ is C(A²), and A² is H.

In one embodiment of Formula (I), D¹ and E¹ are H. In another embodimentof Formula (I), B¹ is NHR¹, and A¹ is C(A²), A² is H, and D¹ and E¹ areH. In another embodiment of Formula (I), B¹ is OR¹, and A¹ is C(A²), A²is H, and D¹ and E¹ are H.

In one embodiment of Formula (I), Y¹ is H, CN, NO₂, F, Cl, Br, I, CF₃,R¹⁷, NHC(O)R¹⁷, or C(O)NH₂. In another embodiment of Formula (I), Y¹ isNO₂. In another embodiment of Formula (I), Y¹ is Cl. In anotherembodiment of Formula (I), B¹ is NHR¹, and A¹ is C(A²), A² is H, D¹ andE¹ are H, and Y¹ is NO₂. In another embodiment of Formula (I), B¹ isOR¹, and A¹ is C(A²), A² is H, D¹ and E¹ are H, and Y¹ is Cl.

In one embodiment of Formula (I), R¹ is R², R³, R⁴ or R⁵. In anotherembodiment of Formula (I), R¹ is R², and R² is phenyl.

In one embodiment of Formula (I), R¹ is R³, and R³ is heteroaryl. Inanother embodiment of Formula (I), R³ is triazolyl.

In one embodiment of Formula (I), R¹ is R⁴. In another embodiment ofFormula (I), R¹ is R⁴, and R⁴ is cycloalkyl. In another embodiment ofFormula (I), R¹ is R⁴, and R⁴ is cyclohexyl. In another embodiment ofFormula (I), R¹ is R⁴, and R⁴ is heterocycloalkyl. In another embodimentof Formula (I), R¹ is R⁴, and R⁴ is 8-azabicyclo[3.2.1]octane,azetidinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,tetrahydropyranyl, or tetrahydrothiophenyl. In another embodiment ofFormula (I), R¹ is R⁴, and R⁴ is heterocycloalkenyl. In anotherembodiment of Formula (I), R¹ is R⁴, and R⁴ is tetrahydropyridazinyl.

In one embodiment of Formula (I), R¹ is R⁵. In another embodiment ofFormula (I), R¹ is R⁵ and R⁵ is alkyl or alkynyl. In another embodimentof Formula (I), R¹ is R⁵ and R⁵ is alkyl which is unsubstituted. Inanother embodiment of Formula (I), R¹ is R⁵ and R⁵ is alkyl which issubstituted with one or two or three independently selected R⁶, R⁷, OR⁷,SR⁷, SO₂R⁷, N(R⁷)₂, OH, CN, CF₃, F, Cl, Br or I substituents. In anotherembodiment of Formula (I), R¹ is R⁵ and R⁵ is alkyl which is substitutedwith R⁷.

In one embodiment of Formula (I), R⁷ is R⁸, R⁹, R¹⁰ or R¹¹. In anotherembodiment of Formula (I), R⁷ is R⁸, and R⁸ is phenyl which is unfusedor fused with R^(8A), and R^(8A) is heterocycloalkane. In anotherembodiment of Formula (I), R⁷ is R⁸, and R⁸ is phenyl which is unfused.In another embodiment of Formula (I), R⁷ is R⁹, and R⁹ is heteroaryl. Inanother embodiment of Formula (I), R⁷ is R⁹, and R⁹ is furanyl,imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl,triazinyl or 1,2,3-triazolyl. In another embodiment of Formula (I), R⁷is R⁹, and R⁹ is pyridinyl, thiazolyl, imidazoyl, and 1,2,3-triazolyl.In another embodiment of Formula (I), R⁷ is R¹⁰, and R¹⁰ isC₃-C₁₀-cycloalkyl. In another embodiment of Formula (I), R⁷ is R¹⁰, andR¹⁰ is C₆ or C₁₀-cycloalkyl. In another embodiment of Formula (I), R⁷ isR¹⁰, and R¹⁰ is cyclohexyl or adamantanyl. In another embodiment ofFormula (I), R⁷ is R¹⁰, and R¹⁰ is morpholinyl, piperazinyl,piperidinyl, tetrahydro-2H-pyranyl, 1,2-dihydropyridinyl, pyranyl,pyridin-1(H)-yl, pyrrolidinyl, oxetanyl, thiomorpholinyl,imidazolidinyl, tetrahydrothiophenyl, dioxolanyl, tetrahydrothiopyranyl,dioxanyl, or tetrahydrofuranyl. In another embodiment of Formula (I), R⁷is R¹⁰, and R¹⁰ is morpholinyl, piperazinyl, piperidinyl,tetrahydro-2H-pyranyl, 1,2-dihydropyridinyl, pyrrolidinyl, oxetanyl,thiomorpholinyl, imidazolidinyl, tetrahydrothiophenyl, dioxolanyl,tetrahydrothiopyranyl, dioxanyl, or tetrahydrofuranyl. In anotherembodiment of Formula (I), R⁷ is R¹¹, and R¹¹ is alkyl which isunsubstituted or substituted. In another embodiment of Formula (I), R⁷is R¹¹, and R¹¹ is alkyl which is unsubstituted. In another embodimentof Formula (I), R⁷ is R¹¹, and R¹¹ is alkyl which is substituted. Inanother embodiment of Formula (I), R⁷ is R¹¹, and R¹¹ is alkyl which issubstituted with one or two or three independently selected OR¹², F, Cl,Br or I substituents. In another embodiment of Formula (I), R⁷ is R¹¹,R¹¹ is alkyl which is substituted with OR¹², R¹² is R¹⁶, and R¹⁶ isalkyl.

In one embodiment of Formula (I), R¹⁷ is R¹⁹ or R²¹. In anotherembodiment of Formula (I), R¹⁷ is R¹⁹, and R¹⁹ is heteroaryl. In anotherembodiment of Formula (I), R¹⁷ is R¹⁹, and R¹⁹ is thiazolyl. In anotherembodiment of Formula (I), R¹⁷ is R²¹, and R²¹ is alkynyl. In anotherembodiment of Formula (I), R¹⁷ is R²¹, and R²¹ is ethynyl.

Still another embodiment pertains to compounds having Formula I whichare

-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;

benzamide;

-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-(benzyloxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(2-phenylethoxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenylthio)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenylthio)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(phenylthio)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenylsulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenylsulfinyl)benzamide;-   2-benzyl-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-benzyl-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-benzyl-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(2-phenylethyl)benzamide;-   2-(benzylamino)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-anilino-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   2-anilino-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-methoxy-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indazol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indazol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(1,2,3,4-tetrahydroquinolin-6-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-(1,2,3,4-tetrahydroquinolin-6-yloxy)benzamide;-   4-(4-((4′-chloro-4-(pyrrolidin-1-ylmethyl)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-cyclopentylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)-3-isobutylpiperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(2,4-dioxo-3-azabicyclo(3.2.0)hept-3-yl)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(3,3-dimethyl-2-oxoazetidin-1-yl)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(4-nitro-2H-1,2,3-triazol-2-yl)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((2-(2-piperidin-1-ylethoxy)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-((((1-ethylpyrrolidin-2-yl)methyl)amino)carbonyl)-4-methoxyphenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1-naphthyloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-naphthyloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-naphthyloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-naphthyloxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(quinolin-7-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(quinolin-6-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(isoquinolin-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(isoquinolin-5-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(quinolin-6-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-6-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(isoquinolin-7-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(isoquinolin-7-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-methoxyphenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-methylphenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   N-((3-((chloro(difluoro)methyl)sulfonyl)-4-((3-(dimethylamino)propyl)amino)phenyl)sulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   2-(1H-indol-4-yloxy)-4-(4-((2-(4-methoxyphenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4,4-dimethyl-2-(4-(trifluoromethyl)phenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4,4-dimethyl-2-(4-(trifluoromethoxy)phenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4,4-dimethyl-2-(3-(trifluoromethyl)phenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(3-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   N-((3-((chloro(difluoro)methyl)sulfonyl)-4-((1-methylpiperidin-4-yl)amino)phenyl)sulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenoxymethyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(pyridin-3-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(pyridin-3-yloxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(pyridin-4-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(pyridin-3-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(pyridin-4-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(4-methylpiperazin-1-yl)propyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)(methyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-cyano-4-((3-(dimethylamino)propyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-(trifluoromethyl)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(isopropyl(methyl)amino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(3-(dimethylamino)propoxy)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-(4-methylpiperazin-1-yl)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-(4-methylpiperazin-1-yl)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(3-(dimethylamino)propoxy)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(3-(dimethylamino)propoxy)-3-nitrophenyl)sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-(4-methylpiperazin-1-yl)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((4-(dimethylamino)-1-methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydro-1,4-benzodioxin-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-1,1′-biphenyl-2-carboxamide;-   5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-1,1′-biphenyl-2-carboxamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-4-(3-piperidin-1-ylpropoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-4-(3-(dimethylamino)propoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(3-piperidin-1-ylpropoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(3-(dimethylamino)propoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-3-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-3-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-4-(2-pyrrolidin-1-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-4-(2-(diisopropylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydro-1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclooct-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclooct-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((2-(dimethylamino)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((4-(dimethylamino)butyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((1-(phenylsulfonyl)piperidin-4-yl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((1-(quinolin-8-ylsulfonyl)piperidin-4-yl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((1-(phenylsulfonyl)piperidin-4-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((1-(quinolin-8-ylsulfonyl)piperidin-4-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(((1S)-3-(dimethylamino)-1-thien-2-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((thien-2-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((2-(1H-1,2,3-triazol-1-yl)ethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((2-(2H-1,2,3-triazol-2-yl)ethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-naphthyloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((2-(2-oxopyridin-1(2H)-yl)ethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((2-(pyridin-2-yloxy)ethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((2-pyridin-4-ylethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-(trifluoromethyl)phenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-cyano-4-((3-(dimethylamino)propyl)amino)phenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((4-methylpiperazin-1-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-(1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   N-((4-(((4-aminotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-3-fluoro-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-3-fluoro-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   N-[(4-{[(3S,4R)-1-benzyl-3-hydroxypiperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-[4-({4′-chloro-3-[3-(dimethylamino)propyl]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-{4-[(4′-chloro-4-morpholin-4-yl-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dimethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(dimethylamino)tetrahydro-2H-pyran-4-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   N-({4-[(2-aminocyclohexyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-[4-({4′-chloro-4-[3-(dimethylamino)prop-1-ynyl]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[1-(4,4,4-trifluorobutyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[2-(4-hydroxy-1-methylpiperidin-4-yl)ethyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-2-yl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[4′-chloro-4-(2-hydroxyethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(4,4,4-trifluorobutyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[4′-chloro-4-(2-hydroxyethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1-morpholin-4-ylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-2-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(2-hydroxyethyl)piperazin-1-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(3-fluoropropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-hydroxy-1-tetrahydro-2H-pyran-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-({1-[2-(1H-pyrazol-1-yl)ethyl]piperidin-4-yl}amino)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(methylamino)-3-nitrophenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(methylamino)-3-nitrophenyl]sulfonyl}benzamide;-   4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-morpholin-4-ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-[(4-{[(1-aminocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxopyrrolidin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-{4-[(1R)-1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-{4-[(1S)-1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-3-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(3-methyloxetan-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methoxycyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(1,1-dioxidothiomorpholin-4-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxopiperidin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxoimidazolidin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2-pyridin-4-ylethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-morpholin-4-yl-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(4-methoxypiperidin-1-yl)-3-nitrophenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-pyrrolidin-1-ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(3-oxopiperazin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-[4-({4′-chloro-4-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1,1-dioxidotetrahydrothien-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-(trifluoromethyl)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[2-(1,3-dioxolan-2-yl)ethyl]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[2-(3-oxopiperazin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methyl-5-oxopyrrolidin-3-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methyl-6-oxopiperidin-3-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(piperidin-1-ylamino)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(piperidin-1-ylamino)phenyl]sulfonyl}benzamide;-   4-(4-{[4-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methyloxetan-3-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(1-oxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1,3-thiazol-5-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2-tetrahydro-2H-pyran-4-ylethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[2-(trifluoromethoxy)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[3-(methylsulfonyl)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(1,1-dioxidothiomorpholin-4-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethyl)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(trifluoromethoxy)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2,2-difluoroethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4,4-difluorocyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethoxy)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[3-(methylsulfonyl)propoxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methoxypropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-methoxypropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(3R)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[Cis-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phenyl}sulfonyl)benzamide;-   N-({5-bromo-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1,1-dioxidotetrahydrothien-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-(methylamino)-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   N-{[5-bromo-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6-isopropoxypyridin-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[6-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(1,3-thiazol-2-yl)pyridin-3-yl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(2-methoxyethyl)amino]carbonyl}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[4′-chloro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[4′-chloro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide;-   4-{4-[(5-tert-butyl-4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-{4-[(5-tert-butyl-4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2S)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   N-({5-bromo-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)oxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-1-(3-hydroxypropyl)-1,2,5,6-tetrahydropyridin-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   benzyl    4-({[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenyl]amino}methyl)piperidine-1-carboxylate;-   N-{[3-(aminocarbonyl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[4′-chloro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-{4-[(5-tert-butyl-4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1-methyl-1H-imidazol-5-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylsulfonyl)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   N-{[5-bromo-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-5-(1,3-thiazol-2-yl)pyridin-3-yl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3,3-dimethylbutyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1S)-1-(hydroxymethyl)-3-methylbutyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R)-1-(hydroxymethyl)-2-methylpropyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methoxyphenyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   N-[(4-{[2-(1,3-benzodioxol-5-yl)ethyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-hydroxyphenyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   N-{[4-({2-[4-(aminosulfonyl)phenyl]ethyl}amino)-3-nitrophenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(1H-imidazol-1-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(1S)-1-phenylethyl]amino}phenyl)sulfonyl]benzamide;-   N-({2-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]thio}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]thio}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(methylsulfonyl)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(methylsulfonyl)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-hydroxy-4-methoxyphenyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-dihydro-1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(pyridin-3-ylamino)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(pyridin-3-ylamino)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(pyridin-3-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1,2,3,4-tetrahydroisoquinolin-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide;-   N-[(5-chloro-6-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   Trans-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2,2-difluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   N-[(5-chloro-6-{[1-(cyanomethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydrofuran-3-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   Trans-N-({5-chloro-6-[(4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(cyanomethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-(2-methoxyethoxy)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(N,N-dimethylglycyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(cyanomethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-oxetan-3-ylmorpholin-2-yl)methyl]amino}phenyl)sulfonyl]benzamide;-   N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}oxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({(2R)-4-[2-(2-methoxyethoxy)ethyl]morpholin-2-yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   N-[(4-{[(4-acetylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methylsulfonyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-({4-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(2-tetrahydrofuran-2-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyanocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-tetrahydro-2H-pyran-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxy-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;-   N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxy-4-(4-{(3-phenylpropanoyl)    [(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;-   N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxy-4-(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;-   N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxy-4-(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;-   4-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)piperazin-1-yl]-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide;-   4-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;-   4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;-   4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide;-   4-(4-{2-[(4R,7S)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoinden-5-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;-   4-[4-(2-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;-   4-[4-(2-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzylidene)piperidin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;-   4-[4-(3-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;    and therapeutically acceptable salts, prodrugs, salts of prodrugs    and metabolites thereof.

In another aspect, the present invention provides compounds of Formula(II)

and therapeutically acceptable salts, prodrugs, salts of prodrugs andmetabolites thereof, wherein A¹, B¹, D¹, E¹, Y¹, R³⁰, and R³⁷ are asdescribed herein for Formula (I), n is 0, 1, 2, or 3; describing thenumber of substituents on R²⁶, and R¹⁰⁰ is as described for substituentson R²⁶.

In one embodiment of Formula (II), A¹ is N. In another embodiment ofFormula (II), A¹ is C(A²). In another embodiment of Formula (II), A¹ isC(A²), and A² is H.

In one embodiment of Formula (II), B¹ is R¹, OR¹, SR¹, SO₂R¹, NHR¹,N(R¹)₂, or C(O)NHR¹. In another embodiment of Formula (II), B¹ is NHR¹.In another embodiment of Formula (II), B¹ is NHR¹, and A¹ is C(A²), andA² is H. In another embodiment of Formula (II), B¹ is OR¹. In anotherembodiment of Formula (II), B¹ is OR¹, and A¹ is C(A²), and A² is H.

In one embodiment of Formula (II), D¹ and E¹ are H. In anotherembodiment of Formula (II), B¹ is NHR¹, and A¹ is C(A²), A² is H, and D¹and E¹ are H. In another embodiment of Formula (II), B¹ is OR¹, and A¹is C(A²), A² is H, and D¹ and E¹ are H.

In one embodiment of Formula (II), Y¹ is H, CN, NO₂, F, Cl, Br, I, CF₃,R¹⁷, NHC(O)R¹⁷, or C(O)NH₂. In another embodiment of Formula (II), Y¹ isNO₂. In another embodiment of Formula (II), B¹ is NHR¹, and A¹ is C(A²),A² is H, D¹ and E¹ are H, and Y¹ is NO₂. In another embodiment ofFormula (II), Y¹ is Cl. In another embodiment of Formula (II), B¹ isOR¹, and A¹ is C(A²), A² is H, D¹ and E¹ are H, and Y¹ is Cl.

In one embodiment of Formula (II), R¹ is R², R³, R⁴ or R⁵. In anotherembodiment of Formula (II), R¹ is R², and R² is phenyl.

In one embodiment of Formula (II), R¹ is R³, and R³ is heteroaryl. Inanother embodiment of Formula (II), R³ is triazolyl.

In one embodiment of Formula (II), R¹ is R⁴. In another embodiment ofFormula (II), R¹ is R⁴, and R⁴ is cycloalkyl. In another embodiment ofFormula (II), R¹ is R⁴, and R⁴ is cyclohexyl. In another embodiment ofFormula (II), R¹ is R⁴, and R⁴ is heterocycloalkyl. In anotherembodiment of Formula (II), R¹ is R⁴, and R⁴ is8-azabicyclo[3.2.1]octane, azetidinyl, piperidinyl, piperazinyl,pyrrolidinyl, morpholinyl, tetrahydropyranyl, or tetrahydrothiophenyl.In another embodiment of Formula (II), R¹ is R⁴, and R⁴ isheterocycloalkenyl. In another embodiment of Formula (II), R¹ is R⁴, andR⁴ is tetrahydropyridazinyl.

In one embodiment of Formula (II), R¹ is R⁵. In another embodiment ofFormula (II), R¹ is R⁵ and R⁵ is alkyl or alkynyl. In another embodimentof Formula (II), R¹ is R⁵ and R⁵ is alkyl which is unsubstituted. Inanother embodiment of Formula (II), R¹ is R⁵ and R⁵ is alkyl which issubstituted with one or two or three independently selected R⁶, R⁷, OR⁷,SR⁷, SO₂R⁷, N(R⁷)₂, OH, CN, CF₃, F, Cl, Br or I substituents. In anotherembodiment of Formula (II), R¹ is R⁵ and R⁵ is alkyl which issubstituted with R⁷.

In one embodiment of Formula (II), R⁷ is R⁸, R⁹, R¹⁰ or R¹¹. In anotherembodiment of Formula (II), R⁷ is R⁸, and R⁸ is phenyl which is unfusedor fused with R^(8A), and R^(8A) is heterocycloalkane. In anotherembodiment of Formula (II), R⁷ is R⁸, and R⁸ is phenyl which is unfused.In another embodiment of Formula (II), R⁷ is R⁹, and R⁹ is heteroaryl.In another embodiment of Formula (II), R⁷ is R⁹, and R⁹ is furanyl,imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl,triazinyl or 1,2,3-triazolyl. In another embodiment of Formula (II), R⁷is R⁹, and R⁹ is pyridinyl, thiazolyl, imidazoyl, and 1,2,3-triazolyl.In another embodiment of Formula (II), R⁷ is R¹⁰, and R¹⁰ isC₃-C₁₀-cycloalkyl. In another embodiment of Formula (II), R⁷ is R¹⁰, andR¹⁰ is C₆ or C₁₀-cycloalkyl. In another embodiment of Formula (II), R⁷is R¹⁰, and R¹⁰ is cyclohexyl or adamantanyl. In another embodiment ofFormula (II), R⁷ is R¹⁰, and R¹⁰ is morpholinyl, piperazinyl,piperidinyl, tetrahydro-2H-pyranyl, 1,2-dihydropyridinyl, pyranyl,pyridin-1(H)-yl, pyrrolidinyl, oxetanyl, thiomorpholinyl,imidazolidinyl, tetrahydrothiophenyl, dioxolanyl, tetrahydrothiopyranyl,dioxanyl, or tetrahydrofuranyl. In another embodiment of Formula (II),R⁷ is R¹⁰, and R¹⁰ is morpholinyl, piperazinyl, piperidinyl,tetrahydro-2H-pyranyl, 1,2-dihydropyridinyl, pyrrolidinyl, oxetanyl,thiomorpholinyl, imidazolidinyl, tetrahydrothiophenyl, dioxolanyl,tetrahydrothiopyranyl, dioxanyl, or tetrahydrofuranyl. In anotherembodiment of Formula (II), R⁷ is R¹¹, and R¹¹ is alkyl which isunsubstituted or substituted. In another embodiment of Formula (II), R⁷is R¹¹, and R¹¹ is alkyl which is unsubstituted. In another embodimentof Formula (II), R⁷ is R¹¹, and R¹¹ is alkyl which is substituted. Inanother embodiment of Formula (II), R⁷ is R¹¹, and R¹¹ is alkyl which issubstituted with one or two or three independently selected OR¹², F, Cl,Br or I substituents. In another embodiment of Formula (II), R⁷ is R¹¹,R¹¹ is alkyl which is substituted with OR¹², R² is R¹⁶, and R¹⁶ isalkyl.

In one embodiment of Formula (II), R¹⁷ is R¹⁹ or R²¹. In anotherembodiment of Formula (II), R¹⁷ is R¹⁹, and R¹⁹ is heteroaryl. Inanother embodiment of Formula (II), R¹⁷ is R¹⁹, and R¹⁹ is thiazolyl. Inanother embodiment of Formula (II), R¹⁷ is R²¹, and R²¹ is alkynyl. Inanother embodiment of Formula (II), R¹⁷ is R²¹, and R²¹ is ethynyl.

Still another embodiment pertains to compounds having Formula II whichare

-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-cyclopentylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   N-((3-((chloro(difluoro)methyl)sulfonyl)-4-((3-(dimethylamino)propyl)amino)phenyl)sulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   N-((3-((chloro(difluoro)methyl)sulfonyl)-4-((1-methylpiperidin-4-yl)amino)phenyl)sulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-(4-methylpiperazin-1-yl)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(3-(dimethylamino)propoxy)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-(4-methylpiperazin-1-yl)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((4-(dimethylamino)-1-methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-3-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydro-1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-(trifluoromethyl)phenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-cyano-4-((3-(dimethylamino)propyl)amino)phenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((4-methylpiperazin-1-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-3-fluoro-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-3-fluoro-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   N-[(4-{[(3S,4R)-1-benzyl-3-hydroxypiperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-5-fluoro-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-5-fluoro-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(dimethylamino)tetrahydro-2H-pyran-4-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   N-({4-[(2-aminocyclohexyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[2-(4-hydroxy-1-methylpiperidin-4-yl)ethyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-2-yl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(4,4,4-trifluorobutyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1-morpholin-4-ylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-2-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(2-hydroxyethyl)piperazin-1-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(3-fluoropropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-hydroxy-1-tetrahydro-2H-pyran-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-({1-[2-(1H-pyrazol-1-yl)ethyl]piperidin-4-yl}amino)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(methylamino)-3-nitrophenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-morpholin-4-ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-[(4-{[(1-aminocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxopyrrolidin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-3-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(3-methyloxetan-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methoxycyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(1,1-dioxidothiomorpholin-4-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxopiperidin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxoimidazolidin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2-pyridin-4-ylethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-morpholin-4-yl-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(4-methoxypiperidin-1-yl)-3-nitrophenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-5-pyrrolidin-1-ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(3-oxopiperazin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1,1-dioxidotetrahydrothien-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-(trifluoromethyl)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[2-(1,3-dioxolan-2-yl)ethyl]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methyl-5-oxopyrrolidin-3-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methyl-6-oxopiperidin-3-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(piperidin-1-ylamino)phenyl]sulfonyl}benzamide;-   4-(4-{[4-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methyloxetan-3-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(1-oxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1,3-thiazol-5-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2-tetrahydro-2H-pyran-4-ylethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethyl)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(trifluoromethoxy)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2,2-difluoroethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4,4-difluorocyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methoxypropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(3R)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(3R)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-(methylamino)-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   N-{[5-bromo-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[4-(4-chlorophenyl)-6-isopropoxypyridin-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[6-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(1,3-thiazol-2-yl)pyridin-3-yl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(2-methoxyethyl)amino]carbonyl}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[4′-chloro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[4′-chloro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide;-   4-{4-[(5-tert-butyl-4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-{4-[(5-tert-butyl-4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2S)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   N-({5-bromo-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)oxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   benzyl    4-({[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenyl]amino}methyl)piperidine-1-carboxylate;-   N-{[3-(aminocarbonyl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[4′-chloro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-{4-[(5-tert-butyl-4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1-methyl-1H-imidazol-5-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylsulfonyl)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3,3-dimethylbutyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1S)-1-(hydroxymethyl)-3-methylbutyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R)-1-(hydroxymethyl)-2-methylpropyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methoxyphenyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   N-[(4-{[2-(1,3-benzodioxol-5-yl)ethyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-hydroxyphenyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   N-{[4-({2-[4-(aminosulfonyl)phenyl]ethyl}amino)-3-nitrophenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(1H-imidazol-1-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(1S)-1-phenylethyl]amino}phenyl)sulfonyl]benzamide;-   N-({2-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]thio}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(methylsulfonyl)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-hydroxy-4-methoxyphenyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;    and therapeutically acceptable salts, prodrugs, salts of prodrugs    and metabolites thereof.

In another aspect, the present invention provides compounds of Formula(III)

and therapeutically acceptable salts, prodrugs, salts of prodrugs andmetabolites thereof, wherein A¹, B¹, D¹, E¹, Y¹, R³⁰, and R³⁷ are asdescribed herein for Formula (I), n is 0, 1, 2, or 3; describing thenumber of substituents on R²⁶, and R¹⁰⁰ is as described for substituentson R²⁶.

In one embodiment of Formula (III), A¹ is N. In another embodiment ofFormula (III), A¹ is C(A²). In another embodiment of Formula (III), A¹is C(A²), and A² is H.

In one embodiment of Formula (III), B¹ is R¹, OR¹, SR¹, SO₂R¹, NHR¹,N(R¹)₂, or C(O)NHR¹. In another embodiment of Formula (III), B¹ is NHR¹.In another embodiment of Formula (III), B¹ is NHR¹, and A¹ is C(A²), andA² is H. In another embodiment of Formula (III), B¹ is OR¹. In anotherembodiment of Formula (III), B¹ is OR¹, and A¹ is C(A²), and A² is H.

In one embodiment of Formula (III), D¹ and E¹ are H. In anotherembodiment of Formula (III), B¹ is NHR¹, and A¹ is C(A²), A² is H, andD¹ and E¹ are H. In another embodiment of Formula (III), B¹ is OR¹, andA¹ is C(A²), A² is H, and D¹ and E¹ are H.

In one embodiment of Formula (III), Y¹ is H, CN, NO₂, F, Cl, Br, I, CF₃,R¹⁷, NHC(O)R¹⁷, or C(O)NH₂. In another embodiment of Formula (III), Y¹is NO₂. In another embodiment of Formula (III), B¹ is NHR¹, and A¹ isC(A²), A² is H, D¹ and E¹ are H, and Y¹ is NO₂. In another embodiment ofFormula (III), Y¹ is Cl. In another embodiment of Formula (III), B¹ isOR¹, and A¹ is C(A²), A² is H, D¹ and E¹ are H, and Y¹ is Cl.

In one embodiment of Formula (III), R¹ is R², R³, R⁴ or R⁵. In anotherembodiment of Formula (III), R¹ is R², and R² is phenyl.

In one embodiment of Formula (III), R¹ is R³, and R³ is heteroaryl. Inanother embodiment of Formula (III), R³ is triazolyl.

In one embodiment of Formula (III), R¹ is R⁴. In another embodiment ofFormula (III), R¹ is R⁴, and R⁴ is cycloalkyl. In another embodiment ofFormula (III), R¹ is R⁴, and R⁴ is cyclohexyl. In another embodiment ofFormula (III), R¹ is R⁴, and R⁴ is heterocycloalkyl. In anotherembodiment of Formula (III), R¹ is R⁴, and R⁴ is8-azabicyclo[3.2.1]octane, azetidinyl, piperidinyl, piperazinyl,pyrrolidinyl, morpholinyl, tetrahydropyranyl, or tetrahydrothiophenyl.In another embodiment of Formula (III), R¹ is R⁴, and R⁴ isheterocycloalkenyl. In another embodiment of Formula (III), R¹ is R⁴,and R⁴ is tetrahydropyridazinyl.

In one embodiment of Formula (III), R¹ is R⁵. In another embodiment ofFormula (III), R¹ is R⁵ and R⁵ is alkyl or alkynyl. In anotherembodiment of Formula (III), R¹ is R⁵ and R⁵ is alkyl which isunsubstituted. In another embodiment of Formula (III), R¹ is R⁵ and R⁵is alkyl which is substituted with one or two or three independentlyselected R⁶, R⁷, OR⁷, SR⁷, SO₂R⁷, N(R⁷)₂, OH, CN, CF₃, F, Cl, Br or Isubstituents. In another embodiment of Formula (III), R¹ is R⁵ and R⁵ isalkyl which is substituted with R⁷.

In one embodiment of Formula (III), R⁷ is R⁸, R⁹, R¹⁰ or R¹¹. In anotherembodiment of Formula (III), R⁷ is R⁸, and R⁸ is phenyl which is unfusedor fused with R^(8A), and R^(8A) is heterocycloalkane. In anotherembodiment of Formula (III), R⁷ is R⁸, and R⁸ is phenyl which isunfused. In another embodiment of Formula (III), R⁷ is R⁹, and R⁹ isheteroaryl. In another embodiment of Formula (III), R⁷ is R⁹, and R⁹ isfuranyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl,triazinyl or 1,2,3-triazolyl. In another embodiment of Formula (III), R⁷is R⁹, and R⁹ is pyridinyl, thiazolyl, imidazoyl, and 1,2,3-triazolyl.In another embodiment of Formula (III), R⁷ is R¹⁰, and R¹⁰ isC₃-C₁₀-cycloalkyl. In another embodiment of Formula (III), R⁷ is R¹⁰,and R¹⁰ is C₆ or Clo-cycloalkyl. In another embodiment of Formula (III),R⁷ is R¹⁰, and R¹⁰ is cyclohexyl or adamantanyl. In another embodimentof Formula (III), R⁷ is R¹⁰, and R¹⁰ is morpholinyl, piperazinyl,piperidinyl, tetrahydro-2H-pyranyl, 1,2-dihydropyridinyl, pyranyl,pyridin-1(H)-yl, pyrrolidinyl, oxetanyl, thiomorpholinyl,imidazolidinyl, tetrahydrothiophenyl, dioxolanyl, tetrahydrothiopyranyl,dioxanyl, or tetrahydrofuranyl. In another embodiment of Formula (III),R⁷ is R¹⁰, and R¹⁰ is morpholinyl, piperazinyl, piperidinyl,tetrahydro-2H-pyranyl, 1,2-dihydropyridinyl, pyrrolidinyl, oxetanyl,thiomorpholinyl, imidazolidinyl, tetrahydrothiophenyl, dioxolanyl,tetrahydrothiopyranyl, dioxanyl, or tetrahydrofuranyl. In anotherembodiment of Formula (III), R⁷ is R¹¹, and R¹¹ is alkyl which isunsubstituted or substituted. In another embodiment of Formula (III), R⁷is R¹¹, and R¹¹ is alkyl which is unsubstituted. In another embodimentof Formula (III), R⁷ is R¹¹, and R¹¹ is alkyl which is substituted. Inanother embodiment of Formula (III), R⁷ is R¹¹, and R¹¹ is alkyl whichis substituted with one or two or three independently selected OR¹², F,Cl, Br or I substituents. In another embodiment of Formula (III), R⁷ isR¹¹, R¹¹ is alkyl which is substituted with OR¹², R¹² is R¹⁶, and R¹⁶ isalkyl.

In one embodiment of Formula (III), R¹⁷ is R¹⁹ or R²¹. In anotherembodiment of Formula (III), R¹⁷ is R¹⁹, and R¹⁹ is heteroaryl. Inanother embodiment of Formula (III), R¹⁷ is R¹⁹, and R¹⁹ is thiazolyl.In another embodiment of Formula (III), R¹⁷ is R²¹, and R²¹ is alkynyl.In another embodiment of Formula (III), R¹⁷ is R²¹, and R²¹ is ethynyl.

Still another embodiment pertains to compounds having Formula (III)which are

-   4-(4-((4′-chloro-4-(pyrrolidin-1-ylmethyl)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;-   2-(1H-indol-4-yloxy)-4-(4-((2-(4-methoxyphenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4,4-dimethyl-2-(4-(trifluoromethyl)phenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4,4-dimethyl-2-(4-(trifluoromethoxy)phenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4,4-dimethyl-2-(3-(trifluoromethyl)phenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(3-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-(4-methylpiperazin-1-yl)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(3-(dimethylamino)propoxy)-3-nitrophenyl)sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((4′-chloro-3-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclooct-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclooct-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;-   4-(4-(1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;-   N-((4-(((4-aminotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-[4-({4′-chloro-3-[3-(dimethylamino)propyl]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-{4-[(4′-chloro-4-morpholin-4-yl-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dimethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-[4-({4′-chloro-4-[3-(dimethylamino)prop-1-ynyl]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[1-(4,4,4-trifluorobutyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[4′-chloro-4-(2-hydroxyethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[4′-chloro-4-(2-hydroxyethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(methylamino)-3-nitrophenyl]sulfonyl}benzamide;-   4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-{4-[(1R)-1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-{4-[(1S)-1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamide;-   4-[4-({4′-chloro-4-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[2-(3-oxopiperazin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(piperidin-1-ylamino)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[2-(trifluoromethoxy)ethyl]amino}phenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[3-(methylsulfonyl)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(1,1-dioxidothiomorpholin-4-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethoxy)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[3-(methylsulfonyl)propoxy]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-methoxypropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phenyl}sulfonyl)benzamide;-   N-({5-bromo-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1,1-dioxidotetrahydrothien-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;-   N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}sulfonyl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;-   4-(4-{[4-(4-chlorophenyl)-1-(3-hydroxypropyl)-1,2,5,6-tetrahydropyridin-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   N-{[5-bromo-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-5-(1,3-thiazol-2-yl)pyridin-3-yl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]thio}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(methylsulfonyl)phenyl]sulfonyl}benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;-   N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;    and therapeutically acceptable salts, prodrugs, salts of prodrugs    and metabolites thereof.

In another aspect, the present invention provides compounds of Formula(IV)

and therapeutically acceptable salts, prodrugs, salts of prodrugs andmetabolites thereof, wherein A¹, B¹, D¹, E¹, Y¹, R³⁰, and R³⁷ are asdescribed herein for Formula (I), n is 0, 1, 2, or 3; describing thenumber of substituents on R²⁶, and R¹⁰⁰ is as described for substituentson R²⁶.

In one embodiment of Formula (IV), A¹ is N. In another embodiment ofFormula (IV), A¹ is C(A²). In another embodiment of Formula (IV), A¹ isC(A²), and A² is H.

In one embodiment of Formula (IV), B¹ is R¹, OR¹, SR¹, SO₂R¹, NHR¹,N(R¹)₂, or C(O)NHR¹. In another embodiment of Formula (IV), B¹ is NHR¹.In another embodiment of Formula (IV), B¹ is NHR¹, and A¹ is C(A²), andA² is H. In another embodiment of Formula (IV), B¹ is OR¹. In anotherembodiment of Formula (IV), B¹ is OR¹, and A¹ is C(A²), and A² is H.

In one embodiment of Formula (IV), D¹ and E¹ are H. In anotherembodiment of Formula (IV), B¹ is NHR¹, and A¹ is C(A²), A² is H, and D¹and E¹ are H. In another embodiment of Formula (IV), B¹ is OR¹, and A¹is C(A²), A² is H, and D¹ and E¹ are H.

In one embodiment of Formula (IV), Y¹ is H, CN, NO₂, F, Cl, Br, I, CF₃,R¹⁷, NHC(O)R¹⁷, or C(O)NH₂. In another embodiment of Formula (IV), Y¹ isNO₂. In another embodiment of Formula (IV), B¹ is NHR¹, and A¹ is C(A²),A² is H, D¹ and E¹ are H, and Y¹ is NO₂. In another embodiment ofFormula (IV), Y¹ is Cl. In another embodiment of Formula (I), B¹ is OR¹,and A¹ is C(A²), A² is H, D¹ and E¹ are H, and Y¹ is Cl.

In one embodiment of Formula (IV), R¹ is R², R³, R⁴ or R⁵. In anotherembodiment of Formula (IV), R¹ is R², and R² is phenyl.

In one embodiment of Formula (IV), R¹ is R³, and R³ is heteroaryl. Inanother embodiment of Formula (IV), R³ is triazolyl.

In one embodiment of Formula (IV), R¹ is R⁴. In another embodiment ofFormula (IV), R¹ is R⁴, and R⁴ is cycloalkyl. In another embodiment ofFormula (IV), R¹ is R⁴, and R⁴ is cyclohexyl. In another embodiment ofFormula (IV), R¹ is R⁴, and R⁴ is heterocycloalkyl. In anotherembodiment of Formula (IV), R¹ is R⁴, and R⁴ is8-azabicyclo[3.2.1]octane, azetidinyl, piperidinyl, piperazinyl,pyrrolidinyl, morpholinyl, tetrahydropyranyl, or tetrahydrothiophenyl.In another embodiment of Formula (IV), R¹ is R⁴, and R⁴ isheterocycloalkenyl. In another embodiment of Formula (IV), R¹ is R⁴, andR⁴ is tetrahydropyridazinyl.

In one embodiment of Formula (IV), R¹ is R⁵. In another embodiment ofFormula (IV), R¹ is R⁵ and R⁵ is alkyl or alkynyl. In another embodimentof Formula (IV), R¹ is R⁵ and R⁵ is alkyl which is unsubstituted. Inanother embodiment of Formula (IV), R¹ is R⁵ and R⁵ is alkyl which issubstituted with one or two or three independently selected R⁶, R⁷, OR⁷,SR⁷, SO₂R⁷, N(R⁷)₂, OH, CN, CF₃, F, Cl, Br or I substituents. In anotherembodiment of Formula (IV), R¹ is R⁵ and R⁵ is alkyl which issubstituted with R⁷.

In one embodiment of Formula (IV), R⁷ is R⁸, R⁹, R¹⁰ or R¹¹. In anotherembodiment of Formula (IV), R⁷ is R⁸, and R⁸ is phenyl which is unfusedor fused with R^(8A), and R^(8A) is heterocycloalkane. In anotherembodiment of Formula (IV), R⁷ is R⁸, and R⁸ is phenyl which is unfused.In another embodiment of Formula (IV), R⁷ is R⁹, and R⁹ is heteroaryl.In another embodiment of Formula (IV), R⁷ is R⁹, and R⁹ is furanyl,imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl,triazinyl or 1,2,3-triazolyl. In another embodiment of Formula (IV), R⁷is R⁹, and R⁹ is pyridinyl, thiazolyl, imidazoyl, and 1,2,3-triazolyl.In another embodiment of Formula (IV), R⁷ is R¹⁰, and R¹⁰ isC₃-C₁₀-cycloalkyl. In another embodiment of Formula (IV), R⁷ is R¹⁰, andR¹⁰ is C₆ or C₁₀-cycloalkyl. In another embodiment of Formula (IV), R⁷is R¹⁰, and R¹⁰ is cyclohexyl or adamantanyl. In another embodiment ofFormula (IV), R⁷ is R¹⁰, and R¹⁰ is morpholinyl, piperazinyl,piperidinyl, tetrahydro-2H-pyranyl, 1,2-dihydropyridinyl, pyranyl,pyridin-1(H)-yl, pyrrolidinyl, oxetanyl, thiomorpholinyl,imidazolidinyl, tetrahydrothiophenyl, dioxolanyl, tetrahydrothiopyranyl,dioxanyl, or tetrahydrofuranyl. In another embodiment of Formula (IV),R⁷ is R¹⁰, and R¹⁰ is morpholinyl, piperazinyl, piperidinyl,tetrahydro-2H-pyranyl, 1,2-dihydropyridinyl, pyrrolidinyl, oxetanyl,thiomorpholinyl, imidazolidinyl, tetrahydrothiophenyl, dioxolanyl,tetrahydrothiopyranyl, dioxanyl, or tetrahydrofuranyl. In anotherembodiment of Formula (IV), R⁷ is R¹¹, and R¹¹ is alkyl which isunsubstituted or substituted. In another embodiment of Formula (IV), R⁷is R¹¹, and R¹¹ is alkyl which is unsubstituted. In another embodimentof Formula (IV), R⁷ is R¹¹, and R¹¹ is alkyl which is substituted. Inanother embodiment of Formula (IV), R⁷ is R¹¹, and R¹¹ is alkyl which issubstituted with one or two or three independently selected OR¹², F, Cl,Br or I substituents. In another embodiment of Formula (IV), R⁷ is R¹¹,R¹¹ is alkyl which is substituted with OR¹², R¹² is R¹⁶, and R¹⁶ isalkyl.

In one embodiment of Formula (IV), R¹⁷ is R¹⁹ or R²¹. In anotherembodiment of Formula (IV), R¹⁷ is R¹⁹, and R¹⁹ is heteroaryl. Inanother embodiment of Formula (IV), R¹⁷ is R¹⁹, and R¹⁹ is thiazolyl. Inanother embodiment of Formula (IV), R¹⁷ is R²¹, and R²¹ is alkynyl. Inanother embodiment of Formula (IV), R¹⁷ is R²¹, and R²¹ is ethynyl.

Still another embodiment pertains to compounds having Formula (IV) whichare

-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2,2-difluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(cyanomethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-(2-methoxyethoxy)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(N,N-dimethylglycyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(cyanomethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-oxetan-3-ylmorpholin-2-yl)methyl]amino}phenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)benzamide;-   Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({(2R)-4-[2-(2-methoxyethoxy)ethyl]morpholin-2-yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   N-[(4-{[(4-acetylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methylsulfonyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;-   Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyanocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;    and therapeutically acceptable salts, prodrugs, salts of prodrugs    and metabolites thereof.

In another aspect, the present invention provides compounds of Formula(V)

and therapeutically acceptable salts, prodrugs, salts of prodrugs andmetabolites thereof, wherein A¹, B¹, D¹, E¹, Y¹, R³⁰, and R³⁷ are asdescribed herein for Formula (I), n is 0, 1, 2, or 3; describing thenumber of substituents on R²⁶, and R¹⁰⁰ is as described for substituentson R²⁶.

In one embodiment of Formula (V), A¹ is N. In another embodiment ofFormula (V), A¹ is C(A²). In another embodiment of Formula (V), A¹ isC(A²), and A² is H.

In one embodiment of Formula (V), B¹ is R¹, OR¹, SR¹, SO₂R¹, NHR¹,N(R¹)₂, or C(O)NHR¹. In another embodiment of Formula (V), B¹ is NHR¹.In another embodiment of Formula (V), B¹ is NHR¹, and A¹ is C(A²), andA² is H. In another embodiment of Formula (V), B¹ is OR¹. In anotherembodiment of Formula (V), B¹ is OR¹, and A¹ is C(A²), and A² is H.

In one embodiment of Formula (V), D¹ and E¹ are H. In another embodimentof Formula (V), B¹ is NHR¹, and A¹ is C(A²), A² is H, and D¹ and E¹ areH. In another embodiment of Formula (V), B¹ is OR¹, and A¹ is C(A²), A²is H, and D¹ and E¹ are H.

In one embodiment of Formula (V), Y¹ is H, CN, NO₂, F, Cl, Br, I, CF₃,R¹⁷, NHC(O)R¹⁷, or C(O)NH₂. In another embodiment of Formula (V), Y¹ isNO₂. In another embodiment of Formula (V), B¹ is NHR¹, and A¹ is C(A²),A² is H, D¹ and E¹ are H, and Y¹ is NO₂. In another embodiment ofFormula (V), Y¹ is Cl. In another embodiment of Formula (I), B¹ is OR¹,and A¹ is C(A²), A² is H, D¹ and E¹ are H, and Y¹ is Cl.

In one embodiment of Formula (V), R¹ is R², R³, R⁴ or R⁵. In anotherembodiment of Formula (V), R¹ is R², and R² is phenyl.

In one embodiment of Formula (V), R¹ is R³, and R³ is heteroaryl. Inanother embodiment of Formula (V), R³ is triazolyl.

In one embodiment of Formula (V), R¹ is R⁴. In another embodiment ofFormula (V), R¹ is R⁴, and R⁴ is cycloalkyl. In another embodiment ofFormula (V), R¹ is R⁴, and R⁴ is cyclohexyl. In another embodiment ofFormula (V), R¹ is R⁴, and R⁴ is heterocycloalkyl. In another embodimentof Formula (V), R¹ is R⁴, and R⁴ is 8-azabicyclo[3.2.1]octane,azetidinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl,tetrahydropyranyl, or tetrahydrothiophenyl. In another embodiment ofFormula (V), R¹ is R⁴, and R⁴ is heterocycloalkenyl. In anotherembodiment of Formula (V), R¹ is R⁴, and R⁴ is tetrahydropyridazinyl.

In one embodiment of Formula (V), R¹ is R⁵. In another embodiment ofFormula (V), R¹ is R⁵ and R⁵ is alkyl or alkynyl. In another embodimentof Formula (V), R¹ is R⁵ and R⁵ is alkyl which is unsubstituted. Inanother embodiment of Formula (V), R¹ is R⁵ and R⁵ is alkyl which issubstituted with one or two or three independently selected R⁶, R⁷, OR⁷,SR⁷, SO₂R⁷, N(R⁷)₂, OH, CN, CF₃, F, Cl, Br or I substituents. In anotherembodiment of Formula (V), R¹ is R⁵ and R⁵ is alkyl which is substitutedwith R⁷.

In one embodiment of Formula (V), R⁷ is R⁸, R⁹, R¹⁰ or R¹¹. In anotherembodiment of Formula (V), R⁷ is R⁸, and R⁸ is phenyl which is unfusedor fused with R^(8A), and R^(8A) is heterocycloalkane. In anotherembodiment of Formula (V), R⁷ is R⁸, and R⁸ is phenyl which is unfused.In another embodiment of Formula (V), R⁷ is R⁹, and R⁹ is heteroaryl. Inanother embodiment of Formula (V), R⁷ is R⁹, and R⁹ is furanyl,imidazolyl, isothiazolyl, isoxazolyl, 1,2,3-oxadiazoyl,1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, thiophenyl,triazinyl or 1,2,3-triazolyl. In another embodiment of Formula (V), R⁷is R⁹, and R⁹ is pyridinyl, thiazolyl, imidazoyl, and 1,2,3-triazolyl.In another embodiment of Formula (V), R⁷ is R¹⁰, and R¹⁰ isC₃-C₁₀-cycloalkyl. In another embodiment of Formula (V), R⁷ is R¹⁰, andR¹⁰ is C₆ or C₁₀-cycloalkyl. In another embodiment of Formula (V), R⁷ isR¹⁰, and R¹⁰ is cyclohexyl or adamantanyl. In another embodiment ofFormula (V), R⁷ is R¹⁰, and R¹⁰ is morpholinyl, piperazinyl,piperidinyl, tetrahydro-2H-pyranyl, 1,2-dihydropyridinyl, pyranyl,pyridin-1(H)-yl, pyrrolidinyl, oxetanyl, thiomorpholinyl,imidazolidinyl, tetrahydrothiophenyl, dioxolanyl, tetrahydrothiopyranyl,dioxanyl, or tetrahydrofuranyl. In another embodiment of Formula (V), R⁷is R¹⁰, and R¹⁰ is morpholinyl, piperazinyl, piperidinyl,tetrahydro-2H-pyranyl, 1,2-dihydropyridinyl, pyrrolidinyl, oxetanyl,thiomorpholinyl, imidazolidinyl, tetrahydrothiophenyl, dioxolanyl,tetrahydrothiopyranyl, dioxanyl, or tetrahydrofuranyl. In anotherembodiment of Formula (V), R⁷ is R¹¹, and R¹¹ is alkyl which isunsubstituted or substituted. In another embodiment of Formula (V), R⁷is R¹¹, and R¹¹ is alkyl which is unsubstituted. In another embodimentof Formula (V), R⁷ is R¹¹, and R¹¹ is alkyl which is substituted. Inanother embodiment of Formula (V), R⁷ is R¹¹, and R¹¹ is alkyl which issubstituted with one or two or three independently selected OR¹², F, Cl,Br or I substituents. In another embodiment of Formula (V), R⁷ is R¹¹,R¹¹ is alkyl which is substituted with OR¹², R¹² is R¹⁶, and R¹⁶ isalkyl.

In one embodiment of Formula (V), R¹⁷ is R¹⁹ or R²¹. In anotherembodiment of Formula (V), R¹⁷ is R¹⁹, and R¹⁹ is heteroaryl. In anotherembodiment of Formula (V), R¹⁷ is R¹⁹, and R¹⁹ is thiazolyl. In anotherembodiment of Formula (V), R¹⁷ is R²¹, and R²¹ is alkynyl. In anotherembodiment of Formula (V), R¹⁷ is R²¹, and R²¹ is ethynyl.

Still another embodiment pertains to compounds having Formula (V) whichare

-   N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide;-   N-[(5-chloro-6-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   Trans-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;-   N-[(5-chloro-6-{[1-(cyanomethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydrofuran-3-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   Trans-N-({5-chloro-6-[(4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}oxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;-   N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-({4-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(2-tetrahydrofuran-2-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;-   N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;-   4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-tetrahydro-2H-pyran-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;    and therapeutically acceptable salts, prodrugs, salts of prodrugs    and metabolites thereof.

Pharmaceutical Compositions, Combination Therapies, Methods ofTreatment, and Administration

Another embodiment comprises pharmaceutical compositions comprising acompound having Formula (I) and an excipient.

Still another embodiment comprises methods of treating cancer in amammal comprising administering thereto a therapeutically acceptableamount of a compound having Formula (I).

Still another embodiment comprises methods of treating autoimmunedisease in a mammal comprising administering thereto a therapeuticallyacceptable amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating diseasesduring which anti-apoptotic Bcl-2 proteins are expressed, saidcompositions comprising an excipient and a therapeutically effectiveamount of the compound having Formula (I).

Still another embodiment pertains to methods of treating disease in apatient during which anti-apoptotic Bcl-2 proteins are expressed, saidmethods comprising administering to the patient a therapeuticallyeffective amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, prostate cancer, small cell lung cancer or spleencancer, said compositions comprising an excipient and a therapeuticallyeffective amount of the compound having Formula (I).

Still another embodiment pertains to methods of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, prostate cancer, small cell lung cancer or spleen cancer in apatient, said methods comprising administering to the patient atherapeutically effective amount of a compound having Formula (I).

Still another embodiment pertains to compositions for treating diseasesduring which are expressed anti-apoptotic Bcl-2 proteins, saidcompositions comprising an excipient and a therapeutically effectiveamount of the compound having Formula (I) and a therapeuticallyeffective amount of one additional therapeutic agent or more than oneadditional therapeutic agent.

Still another embodiment pertains to methods of treating disease in apatient during which are expressed anti-apoptotic Bcl-2 proteins, saidmethods comprising administering to the patient a therapeuticallyeffective amount of a compound having Formula (I) and a therapeuticallyeffective amount of one additional therapeutic agent or more than oneadditional therapeutic agent.

Still another embodiment pertains to compositions for treating bladdercancer, brain cancer, breast cancer, bone marrow cancer, cervicalcancer, chronic lymphocytic leukemia, colorectal cancer, esophagealcancer, hepatocellular cancer, lymphoblastic leukemia, follicularlymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma,myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-smallcell lung cancer, chronic lymphocytic leukemia, myeloma, prostatecancer, small cell lung cancer or spleen cancer, said compositionscomprising an excipient and a therapeutically effective amount of thecompound having Formula (I) and a therapeutically effective amount ofone additional therapeutic agent or more than one additional therapeuticagent.

Still another embodiment pertains to methods of treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer in a patient, said methods comprisingadministering to the patient a therapeutically effective amount of thecompound having Formula (I) and a therapeutically effective amount ofone additional therapeutic agent or more than one additional therapeuticagent.

Metabolites of compounds having Formula I, produced by in vitro or invivo metabolic processes, may also have utility for treating diseasesassociated with anti-apoptotic Bcl-2 protein.

Certain precursor compounds which may be metabolized in vitro or in vivoto form compounds having Formula I may also have utility for treatingdiseases associated with expression of anti-apoptotic Bcl-2 protein.

Compounds having Formula I may exist as acid addition salts, basicaddition salts or zwitterions. Salts of the compounds are preparedduring isolation or following purification of the compounds. Acidaddition salts of the compounds are those derived from the reaction ofthe compounds with an acid. For example, the acetate, adipate, alginate,bicarbonate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,butyrate, camphorate, camphorsulfonate, digluconate, formate, fumarate,glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate,hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate,maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate,nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate,propionate, succinate, tartrate, thiocyanate, trichloroacetic,trifluoroacetic, para-toluenesulfonate, and undecanoate salts of thecompounds and prodrugs thereof are contemplated as being embraced bythis invention. Basic addition salts of the compounds are those derivedfrom the reaction of the compounds with the hydroxide, carbonate orbicarbonate of cations such as lithium, sodium, potassium, calcium, andmagnesium.

The compounds having Formula I may be administered, for example,bucally, ophthalmically, orally, osmotically, parenterally(intramuscularly, intraperitoneally intrasternally, intravenously,subcutaneously), rectally, topically, transdermally, or vaginally.

Therapeutically effective amounts of compounds having Formula I dependon the recipient of the treatment, the disorder being treated and theseverity thereof, the composition containing the compound, the time ofadministration, the route of administration, the duration of treatment,the compound potency, its rate of clearance and whether or not anotherdrug is co-administered. The amount of a compound of this inventionhaving Formula I used to make a composition to be administered daily toa patient in a single dose or in divided doses is from about 0.03 toabout 200 mg/kg body weight. Single dose compositions contain theseamounts or a combination of submultiples thereof.

Compounds having Formula I may be administered with or without anexcipient. Excipients include, for example, encapsulating materials oradditives such as absorption accelerators, antioxidants, binders,buffers, coating agents, coloring agents, diluents, disintegratingagents, emulsifiers, extenders, fillers, flavoring agents, humectants,lubricants, perfumes, preservatives, propellants, releasing agents,sterilizing agents, sweeteners, solubilizers, wetting agents andmixtures thereof.

Excipients for preparation of compositions comprising a compound havingFormula I to be administered orally in solid dosage form include, forexample, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzylbenzoate, 1,3-butylene glycol, carbomers, castor oil, cellulose,cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil,cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl laureate,ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol,groundnut oil, hydroxypropylmethyl cellulose, isopropanol, isotonicsaline, lactose, magnesium hydroxide, magnesium stearate, malt,mannitol, monoglycerides, olive oil, peanut oil, potassium phosphatesalts, potato starch, povidone, propylene glycol, Ringer's solution,safflower oil, sesame oil, sodium carboxymethyl cellulose, sodiumphosphate salts, sodium lauryl sulfate, sodium sorbitol, soybean oil,stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth,tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula I to be administered ophthalmically or orallyin liquid dosage forms include, for example, 1,3-butylene glycol, castoroil, corn oil, cottonseed oil, ethanol, fatty acid esters of sorbitan,germ oil, groundnut oil, glycerol, isopropanol, olive oil, polyethyleneglycols, propylene glycol, sesame oil, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula I to be administered osmotically include, forexample, chlorofluorohydrocarbons, ethanol, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula I to be administered parenterally include, forexample, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose,germ oil, groundnut oil, liposomes, oleic acid, olive oil, peanut oil,Ringer's solution, safflower oil, sesame oil, soybean oil, U.S.P. orisotonic sodium chloride solution, water and mixtures thereof.Excipients for preparation of compositions comprising a compound of thisinvention having Formula I to be administered rectally or vaginallyinclude, for example, cocoa butter, polyethylene glycol, wax andmixtures thereof.

Compounds having Formula (I) are expected to be useful when used withalkylating agents, angiogenesis inhibitors, antibodies, antimetabolites,antimitotics, antiproliferatives, antivirals, aurora kinase inhibitors,other apoptosis promoters (for example, Bcl-xL, Bcl-w and Bfl-1)inhibitors, activators of death receptor pathway, Bcr-Ab1 kinaseinhibitors, BiTE (Bi-Specific T cell Engager) antibodies, antibody drugconjugates, biologic response modifiers, cyclin-dependent kinaseinhibitors, cell cycle inhibitors, cyclooxygenase-2 inhibitors, DVDs,leukemia viral oncogene homolog (ErbB2) receptor inhibitors, growthfactor inhibitors, heat shock protein (HSP)-90 inhibitors, histonedeacetylase (HDAC) inhibitors, hormonal therapies, immunologicals,inhibitors of inhibitors of apoptosis proteins (IAPs), intercalatingantibiotics, kinase inhibitors, kinesin inhibitors, Jak2 inhibitors,mammalian target of rapamycin inhibitors, microRNA's, mitogen-activatedextracellular signal-regulated kinase inhibitors, multivalent bindingproteins, non-steroidal anti-inflammatory drugs (NSAIDs), poly ADP(adenosine diphosphate)-ribose polymerase (PARP) inhibitors, platinumchemotherapeutics, polo-like kinase (Plk) inhibitors, phosphoinositide-3kinase (PI3K) inhibitors, proteosome inhibitors, purine analogs,pyrimidine analogs, receptor tyrosine kinase inhibitors,etinoids/deltoids plant alkaloids, small inhibitory ribonucleic acids(siRNAs), topoisomerase inhibitors, ubiquitin ligase inhibitors, and thelike, and in combination with one or more of these agents.

BiTE antibodies are bi-specific antibodies that direct T-cells to attackcancer cells by simultaneously binding the two cells. The T-cell thenattacks the target cancer cell. Examples of BiTE antibodies includeadecatumumab (Micromet MT201), blinatumomab (Micromet MT103) and thelike. Without being limited by theory, one of the mechanisms by whichT-cells elicit apoptosis of the target cancer cell is by exocytosis ofcytolytic granule components, which include perforin and granzyme B. Inthis regard, Bcl-2 has been shown to attenuate the induction ofapoptosis by both perforin and granzyme B. These data suggest thatinhibition of Bcl-2 could enhance the cytotoxic effects elicited byT-cells when targeted to cancer cells (V. R. Sutton, D. L. Vaux and J.A. Trapani, J. of Immunology 1997, 158 (12), 5783).

SiRNAs are molecules having endogenous RNA bases or chemically modifiednucleotides. The modifications do not abolish cellular activity, butrather impart increased stability and/or increased cellular potency.Examples of chemical modifications include phosphorothioate groups,2′-deoxynucleotide, 2′-OCH₃-containing ribonucleotides,2′-F-ribonucleotides, 2′-methoxyethyl ribonucleotides, combinationsthereof and the like. The siRNA can have varying lengths (e.g., 10-200bps) and structures (e.g., hairpins, single/double strands, bulges,nicks/gaps, mismatches) and are processed in cells to provide activegene silencing. A double-stranded siRNA (dsRNA) can have the same numberof nucleotides on each strand (blunt ends) or asymmetric ends(overhangs). The overhang of 1-2 nucleotides can be present on the senseand/or the antisense strand, as well as present on the 5′- and/or the3′-ends of a given strand. For example, siRNAs targeting Mcl-1 have beenshown to enhance the activity of ABT-263, (i.e.,N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide)or ABT-737 (i.e.,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)in multiple tumor cell lines (Tse et. al, Cancer Research 2008, 68(9),3421 and references therein).

Multivalent binding proteins are binding proteins comprising two or moreantigen binding sites. Multivalent binding proteins are engineered tohave the three or more antigen binding sites and are generally notnaturally occurring antibodies. The term “multispecific binding protein”means a binding protein capable of binding two or more related orunrelated targets. Dual variable domain (DVD) binding proteins aretetravalent or multivalent binding proteins binding proteins comprisingtwo or more antigen binding sites. Such DVDs may be monospecific (i.e.,capable of binding one antigen) or multispecific (i.e., capable ofbinding two or more antigens). DVD binding proteins comprising two heavychain DVD polypeptides and two light chain DVD polypeptides are referredto as DVD Ig's. Each half of a DVD Ig comprises a heavy chain DVDpolypeptide, a light chain DVD polypeptide, and two antigen bindingsites. Each binding site comprises a heavy chain variable domain and alight chain variable domain with a total of 6 CDRs involved in antigenbinding per antigen binding site. Multispecific DVDs include DVD bindingproteins that bind DLL4 and VEGF, or C-met and EFGR or ErbB3 and EGFR.

Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone,bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU),chlorambucil, CLORETAZINE® (laromustine, VNP 40101M), cyclophosphamide,decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide,KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol,mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine,temozolomide, thiotepa, TREANDA® (bendamustine), treosulfan, rofosfamideand the like.

Angiogenesis inhibitors include endothelial-specific receptor tyrosinekinase (Tie-2) inhibitors, epidermal growth factor receptor (EGFR)inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, matrixmetalloproteinase-2 (MMP-2) inhibitors, matrix metalloproteinase-9(MMP-9) inhibitors, platelet-derived growth factor receptor (PDGFR)inhibitors, thrombospondin analogs, vascular endothelial growth factorreceptor tyrosine kinase (VEGFR) inhibitors and the like.

Antimetabolites include ALIMTA® (pemetrexed disodium, LY231514, MTA),5-azacitidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine),clofarabine, cytarabine, cytarabine ocfosfate, cytosine arabinoside,decitabine, deferoxamine, doxifluridine, eflornithine, EICAR(5-ethynyl-1-β-D-ribofuranosylimidazole-4-carboxamide), enocitabine,ethnylcytidine, fludarabine, 5-fluorouracil alone or in combination withleucovorin, GEMZAR® (gemcitabine), hydroxyurea, ALKERAN® (melphalan),mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolicacid, nelarabine, nolatrexed, ocfosfate, pelitrexol, pentostatin,raltitrexed, Ribavirin, triapine, trimetrexate, S-1, tiazofurin,tegafur, TS-1, vidarabine, UFT and the like.

Antivirals include ritonavir, hydroxychloroquine and the like.

Aurora kinase inhibitors include ABT-348, AZD-1152, MLN-8054, VX-680,Aurora A-specific kinase inhibitors, Aurora B-specific kinase inhibitorsand pan-Aurora kinase inhibitors and the like.

Bcl-2 protein inhibitors include AT-101 ((−)gossypol), GENASENSE® (G3139or oblimersen (Bcl-2-targeting antisense oligonucleotide)), IPI-194,IPI-565,N-(4-(4-((4′-chloro(1,1′-biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide)(ABT-737),N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide(ABT-263), GX-070 (obatoclax) and the like.

Bcr-Abl kinase inhibitors include DASATINIB® (BMS-354825), GLEEVEC®(imatinib) and the like.

CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584,flavopyridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib(CYC-202, R-roscovitine), ZK-304709 and the like.

COX-2 inhibitors include ABT-963, ARCOXIA® (etoricoxib), BEXTRA®(valdecoxib), BMS347070, CELEBREX® (celecoxib), COX-189 (lumiracoxib),CT-3, DERAMAXX® (deracoxib), JTE-522,4-methyl-2-(3,4-dimethylphenyl)-1-(4-sulfamoylphenyl-1H-pyrrole), MK-663(etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016,S-2474, T-614, VIOXX® (rofecoxib) and the like.

EGFR inhibitors include ABX-EGF, anti-EGFR immunoliposomes, EGF-vaccine,EMD-7200, ERBITUX® (cetuximab), HR3, IgA antibodies, IRESSA®(gefitinib), TARCEVA® (erlotinib or OSI-774), TP-38, EGFR fusionprotein, TYKERB® (lapatinib) and the like.

ErbB2 receptor inhibitors include CP-724-714, CI-1033 (canertinib),HERCEPTIN® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4,petuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166,dHER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), anti-HER/2neu bispecificantibody, B7.her2IgG3, AS HER2 trifunctional bispecfic antibodies, mABAR-209, mAB 2B-1 and the like.

Histone deacetylase inhibitors include depsipeptide, LAQ-824, MS-275,trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid andthe like.

HSP-90 inhibitors include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010,CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB® (humanrecombinant antibody to HSP-90), NCS-683664, PU24FC1, PU-3, radicicol,SNX-2112, STA-9090 VER49009 and the like.

Inhibitors of inhibitors of apoptosis proteins include HGS1029,GDC-0145, GDC-0152, LCL-161, LBW-242 and the like.

Antibody drug conjugates include anti-CD22-MC-MMAF, anti-CD22-MC-MMAE,anti-CD22-MCC-DM1, CR-011-vcMMAE, PSMA-ADC, MEDI-547, SGN-19Am SGN-35,SGN-75 and the like

Activators of death receptor pathway include TRAIL, antibodies or otheragents that target TRAIL or death receptors (e.g., DR4 and DR5) such asApomab, conatumumab, ETR2-ST01, GDC0145, (lexatumumab), HGS-1029,LBY-135, PRO-1762 and trastuzumab.

Kinesin inhibitors include Eg5 inhibitors such as AZD4877, ARRY-520;CENPE inhibitors such as GSK923295A and the like.

JAK-2 inhibitors include CEP-701 (lesaurtinib), XL019 and INCB018424 andthe like.

MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 andthe like.

mTOR inhibitors include AP-23573, CCI-779, everolimus, RAD-001,rapamycin, temsirolimus, ATP-competitive TORC1/TORC2 inhibitors,including PI-103, PP242, PP30, Torin 1 and the like.

Non-steroidal anti-inflammatory drugs include AMIGESIC® (salsalate),DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (ketoprofen),RELAFEN® (nabumetone), FELDENE® (piroxicam), ibuprofen cream, ALEVE®(naproxen) and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN®(indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE®(etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like.

PDGFR inhibitors include C-451, CP-673, CP-868596 and the like.

Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin)eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin),satraplatin, picoplatin and the like.

Polo-like kinase inhibitors include BI-2536 and the like.

Phosphoinositide-3 kinase (PI3K) inhibitors include wortmannin,LY294002, XL-147, CAL-120, ONC-21, AEZS-127, ETP-45658, PX-866,GDC-0941, BGT226, BEZ235, XL765 and the like.

Thrombospondin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and thelike.

VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788,ANGIOZYME™ (a ribozyme that inhibits angiogenesis (RibozymePharmaceuticals (Boulder, Colo.) and Chiron, (Emeryville, Calif.)),axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, MACUGEN (pegaptamib),NEXAVAR (sorafenib, BAY43-9006), pazopanib (GW-786034), vatalanib(PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap, ZACTIMA™(vandetanib, ZD-6474), GA101, ofatumumab, ABT-806 (mAb-806), ErbB3specific antibodies, BSG2 specific antibodies, DLL4 specific antibodiesand C-met specific antibodies, and the like.

Antibiotics include intercalating antibiotics aclarubicin, actinomycinD, amrubicin, annamycin, adriamycin, BLENOXANE® (bleomycin),daunorubicin, CAELYX® or MYOCET® (liposomal doxorubicin), elsamitrucin,epirbucin, glarbuicin, ZAVEDOS®(idarubicin), mitomycin C, nemorubicin,neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer,streptozocin, VALSTAR® (valrubicin), zinostatin and the like.

Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin,amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR®(irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxine),diflomotecan, edotecarin, ELLENCE® or PHARMORUBICIN® (epirubicin),etoposide, exatecan, 10-hydroxycamptothecin, gimatecan, lurtotecan,mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane,SN-38, tafluposide, topotecan and the like.

Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies,chTNT-1/B, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab),IGF1R-specific antibodies, lintuzumab, PANOREX® (edrecolomab), RENCAREX®(WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab, CD20antibodies types I and II and the like.

Hormonal therapies include ARIMIDEX® (anastrozole), AROMASIN®(exemestane), arzoxifene, CASODEX®(bicalutamide), CETROTIDE®(cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane),dexamethasone, DROGENIL® (flutamide), EVISTA® (raloxifene), AFEMA™(fadrozole), FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA®(letrozole), formestane, glucocorticoids, HECTOROL® (doxercalciferol),RENAGEL® (sevelamer carbonate), lasofoxifene, leuprolide acetate,MEGACE® (megesterol), MIFEPREX® (mifepristone), NILANDRON™ (nilutamide),NOLVADEX® (tamoxifen citrate), PLENAXIS™ (abarelix), prednisone,PROPECIA® (finasteride), rilostane, SUPREFACT® (buserelin), TRELSTAR®(luteinizing hormone releasing hormone (LHRH)), VANTAS® (Histrelinimplant), VETORYL® (trilostane or modrastane), ZOLADEX® (fosrelin,goserelin) and the like.

Deltoids and retinoids include seocalcitol (EB1089, CB1093),lexacalcitrol (KH1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN®(liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like.

PARP inhibitors include ABT-888 (veliparib), olaparib, KU-59436,AZD-2281, AG-014699, BSI-201, BGP-15, INO-1001, ONO-2231 and the like.

Plant alkaloids include, but are not limited to, vincristine,vinblastine, vindesine, vinorelbine and the like.

Proteasome inhibitors include VELCADE® (bortezomib), MG132, NPI-0052,PR-171 and the like.

Examples of immunologicals include interferons and otherimmune-enhancing agents.

Interferons include interferon alpha, interferon alpha-2a, interferonalpha-2b, interferon beta, interferon gamma-1a, ACTIMMUNE® (interferongamma-1b) or interferon gamma-n1, combinations thereof and the like.Other agents include ALFAFERONE®, (IFN-α), BAM-002 (oxidizedglutathione), BEROMUN® (tasonermin), BEXXAR® (tositumomab), CAMPATH®(alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine,denileukin, epratuzumab, GRANOCYTE® (lenograstim), lentinan, leukocytealpha interferon, imiquimod, MDX-010 (anti-CTLA-4), melanoma vaccine,mitumomab, molgramostim, MYLOTARG™ (gemtuzumab ozogamicin), NEUPOGEN®(filgrastim), OncoVAC-CL, OVAREX® (oregovomab), pemtumomab (Y-muHMFGi),PROVENGE® (sipuleucel-T), sargaramostim, sizofilan, teceleukin,THERACYS® (Bacillus Calmette-Guerin), ubenimex, VIRULIZIN®(immunotherapeutic, Lorus Pharmaceuticals), Z-100 (Specific Substance ofMaruyama (SSM)), WF-10 (Tetrachlorodecaoxide (TCDO)), PROLEUKIN®(aldesleukin), ZADAXIN® (thymalfasin), ZENAPAX® (daclizumab), ZEVALIN®(90Y-Ibritumomab tiuxetan) and the like.

Biological response modifiers are agents that modify defense mechanismsof living organisms or biological responses, such as survival, growth ordifferentiation of tissue cells to direct them to have anti-tumoractivity and include krestin, lentinan, sizofuran, picibanil PF-3512676(CpG-8954), ubenimex and the like.

Pyrimidine analogs include cytarabine (ara C or Arabinoside C), cytosinearabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU(5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX®(ratitrexed), TROXATYL™ (triacetyluridine troxacitabine) and the like.

Purine analogs include LANVIS® (thioguanine) and PURI-NETHOL®(mercaptopurine).

Antimitotic agents include batabulin, epothilone D (KOS-862),N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-methoxybenzenesulfonamide,ixabepilone (BMS 247550), paclitaxel, TAXOTERE® (docetaxel), PNU100940(109881), patupilone, XRP-9881 (larotaxel), vinflunine, ZK-EPO(synthetic epothilone) and the like.

Ubiquitin ligase inhibitors include MDM2 inhibitors, such as nutlins,NEDD8 inhibitors such as MLN4924 and the like.

Compounds of this invention can also be used as radiosensitizers thatenhance the efficacy of radiotherapy. Examples of radiotherapy includeexternal beam radiotherapy, teletherapy, brachytherapy and sealed,unsealed source radiotherapy and the like.

Additionally, compounds having Formula (I) may be combined with otherchemotherapeutic agents such as ABRAXANE™ (ABI-007), ABT-100 (farnesyltransferase inhibitor), ADVEXIN® (Ad5CMV-p53 vaccine), ALTOCOR® orMEVACOR® (lovastatin), AMPLIGEN® (poly I:poly C12U, a synthetic RNA),APTOSYN® (exisulind), AREDIA® (pamidronic acid), arglabin,L-asparaginase, atamestane (1-methyl-3,17-dione-androsta-1,4-diene),AVAGE® (tazarotene), AVE-8062 (combreastatin derivative) BEC2(mitumomab), cachectin or cachexin (tumor necrosis factor), canvaxin(vaccine), CEAVAC® (cancer vaccine), CELEUK® (celmoleukin), CEPLENE®(histamine dihydrochloride), CERVARIX® (human papillomavirus vaccine),CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN®(hydroxydoxorubicin); O: Vincristine (ONCOVIN®); P: prednisone), CYPAT™(cyproterone acetate), combrestatin A4P, DAB(389)EGF (catalytic andtranslocation domains of diphtheria toxin fused via a His-Ala linker tohuman epidermal growth factor) or TransMID-107R™ (diphtheria toxins),dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA),eniluracil, EVIZON™ (squalamine lactate), DIMERICINE® (T4N5 liposomelotion), discodermolide, DX-8951f (exatecan mesylate), enzastaurin,EP0906 (epithilone B), GARDASIL® (quadrivalent human papillomavirus(Types 6, 11, 16, 18) recombinant vaccine), GASTRIMMUNE®, GENASENSE®,GMK (ganglioside conjugate vaccine), GVAX® (prostate cancer vaccine),halofuginone, histerelin, hydroxycarbamide, ibandronic acid, IGN-101,IL-13-PE38, IL-13-PE38QQR (cintredekin besudotox), IL-13-pseudomonasexotoxin, interferon-α, interferon-γ, JUNOVAN™ or MEPACT™ (mifamurtide),lonafarnib, 5,10-methylenetetrahydrofolate, miltefosine(hexadecylphosphocholine), NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexateglucuronate), NIPENT® (pentostatin), ONCONASE® (a ribonuclease enzyme),ONCOPHAGE® (melanoma vaccine treatment), ONCOVAX® (IL-2 Vaccine),ORATHECIN™ (rubitecan), OSIDEM® (antibody-based cell drug), OVAREX® MAb(murine monoclonal antibody), paclitaxel, PANDIMEX™ (aglycone saponinsfrom ginseng comprising 20(S)protopanaxadiol (aPPD) and20(S)protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigationalcancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol,procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID®(lenalidomide), RSR13 (efaproxiral), SOMATULINE® LA (lanreotide),SORIATANE® (acitretin), staurosporine (Streptomyces staurospores),talabostat (PT100), TARGRETIN® (bexarotene), TAXOPREXIN®(DHA-paclitaxel), TELCYTA® (canfosfamide, TLK286), temilifene, TEMODAR®(temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-KLH), thymitaq(2-amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)quinazolinedihydrochloride), TNFERADE™ (adenovector: DNA carrier containing thegene for tumor necrosis factor-α), TRACLEER® or ZAVESCA® (bosentan),tretinoin (Retin-A), tetrandrine, TRISENOX® (arsenic trioxide),VIRULIZIN®, ukrain (derivative of alkaloids from the greater celandineplant), vitaxin (anti-alphavbeta3 antibody), XCYTRIN® (motexafingadolinium), XINLAY™ (atrasentan), XYOTAX™ (paclitaxel poliglumex),YONDELIS® (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), ZOMETA®(zolendronic acid), zorubicin and the like.

Data

Determination of the utility of compounds having Formula I as binders toand inhibitors of anti-apoptotic Bcl-2 and Bcl-xL proteins was performedusing the Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET)Assay. Tb-anti-GST antibody was purchased from Invitrogen (Catalog No.PV4216).

Probe Synthesis

All reagents were used as obtained from the vendor unless otherwisespecified. Peptide synthesis reagents including diisopropylethylamine(DIEA), dichloromethane (DCM), N-methylpyrrolidone (NMP),2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU), N-hydroxybenzotriazole (HOBt) and piperidine were obtained fromApplied Biosystems, Inc. (ABI), Foster City, Calif. or AmericanBioanalytical, Natick, Mass. Preloaded 9-Fluorenylmethyloxycarbonyl(Fmoc) amino acid cartridges (Fmoc-Ala-OH, Fmoc-Cys(Trt)-OH,Fmoc-Asp(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Phe-OH, Fmoc-Gly-OH,Fmoc-His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH,Fmoc-Met-OH, Fmoc-Asn(Trt)-OH, Fmoc-Pro-OH, Fmor-Gln(Trt)-OH,Fmoc-Arg(Pbf)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH,Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH) were obtained from ABI or Anaspec,San Jose, Calif. The peptide synthesis resin (Fmoc-Rink amide MBHAresin) and Fmoc-Lys(Mtt)-OH were obtained from Novabiochem, San Diego,Calif. Single-isomer 6-carboxyfluorescein succinimidyl ester (6-FAM-NHS)was obtained from Anaspec. Trifluoroacetic acid (TFA) was obtained fromOakwood Products, West Columbia, S.C. Thioanisole, phenol,triisopropylsilane (TIS), 3,6-dioxa-1,8-octanedithiol (DODT) andisopropanol were obtained from Aldrich Chemical Co., Milwaukee, Wis.Matrix-assisted laser desorption ionization mass-spectra (MALDI-MS) wererecorded on an Applied Biosystems Voyager DE-PRO MS). Electrospraymass-spectra (ESI-MS) were recorded on Finnigan SSQ7000 (Finnigan Corp.,San Jose, Calif.) in both positive and negative ion mode.

General Procedure for Solid-Phase Peptide Synthesis (SPPS)

Peptides were synthesized with, at most, 250 mol preloaded Wangresin/vessel on an ABI 433A peptide synthesizer using 250 μmol scaleFastmoc™ coupling cycles. Preloaded cartridges containing 1 mmolstandard Fmoc-amino acids, except for the position of attachment of thefluorophore, where 1 mmol Fmoc-Lys(Mtt)-OH was placed in the cartridge,were used with conductivity feedback monitoring. N-terminal acetylationwas accomplished by using 1 mmol acetic acid in a cartridge understandard coupling conditions.

Removal of 4-Methyltrityl (Mtt) from Lysine

The resin from the synthesizer was washed thrice with dichloromethaneand kept wet. 150 mL of 95:4:1dichloromethane:triisopropylsilane:trifluoroacetic acid was flowedthrough the resin bed over 30 minutes. The mixture turned deep yellowthen faded to pale yellow. 100 mL of DMF was flowed through the bed over15 minutes. The resin was then washed thrice with DMF and filtered.Ninhydrin tests showed a strong signal for primary amine.

Resin Labeling with 6-Carboxyfluorescein-NHS (6-FAM-NHS)

The resin was treated with 2 equivalents 6-FAM-NHS in 1% DIEA/DMF andstirred or shaken at ambient temperature overnight. When complete, theresin was drained, washed thrice with DMF, thrice with (1% DCM and 1%methanol) and dried to provide an orange resin that was negative byninhydrin test.

General Procedure for Cleavage and Deprotection of Resin-Bound Peptide

Peptides were cleaved from the resin by shaking for 3 hours at ambienttemperature in a cleavage cocktail consisting of 80% TFA, 5% water, 5%thioanisole, 5% phenol, 2.5% TIS, and 2.5% EDT (1 mL/0.1 g resin). Theresin was removed by filtration and rinsing twice with TFA. The TFA wasevaporated from the filtrates, and product was precipitated with ether(10 mL/0.1 g resin), recovered by centrifugation, washed twice withether (10 mL/0.1 g resin) and dried to give the crude peptide.

General Procedure for Purification of Peptides

The crude peptides were purified on a Gilson preparative HPLC systemrunning Unipoint® analysis software (Gilson, Inc., Middleton, Wis.) on aradial compression column containing two 25×100 mm segments packed withDelta-Pak™ C18 15 μm particles with 100 Å pore size and eluted with oneof the gradient methods listed below. One to two milliliters of crudepeptide solution (10 mg/mL in 90% DMSO/water) was purified perinjection. The peaks containing the product(s) from each run were pooledand lyophilized. All preparative runs were run at 20 mL/min with eluentsas buffer A: 0.1% TFA-water and buffer B: acetonitrile.

General Procedure for Analytical HPLC

Analytical HPLC was performed on a Hewlett-Packard 1200 series systemwith a diode-array detector and a Hewlett-Packard 1046A fluorescencedetector running HPLC 3D ChemStation software version A.03.04(Hewlett-Packard. Palo Alto, Calif.) on a 4.6×250 mm YMC column packedwith ODS-AQ 5 μm particles with a 120 Å pore size and eluted with one ofthe gradient methods listed below after preequilibrating at the startingconditions for 7 minutes. Eluents were buffer A: 0.1% TFA-water andbuffer B: acetonitrile. The flow rate for all gradients was 1 mL/min.

(SEQ ID NO: 1) F-Bak: Peptide Probe: Acetyl-- GQVGRQLAIIGDK(6-FAM)-(SEQ ID NO: 2) INR-NH₂

Fmoc-Rink amide MBHA resin was extended using the general peptidesynthesis procedure to provide the protected resin-bound peptide (1.020g). The Mtt group was removed, labeled with 6-FAM-NHS and cleaved anddeprotected as described hereinabove to provide the crude product as anorange solid (0.37 g). This product was purified by RP-HPLC. Fractionsacross the main peak were tested by analytical RP-HPLC, and the purefractions were isolated and lyophilized, with the major peak providingthe title compound (0.0802 g) as a yellow solid; MALDI-MS m/z=2137.1((M+H)⁺).

Alternative Synthesis of Peptide Probe F-Bak: (SEQ ID NO: 1)Acetyl--GQVGRQLAIIGDK(6-FAM)-- (SEQ ID NO: 2) INR-NH₂

The protected peptide was assembled on 0.25 mmol Fmoc-Rink amide MBHAresin (Novabiochem) on an Applied Biosystems 433A automated peptidesynthesizer running Fastmoc™ coupling cycles using pre-loaded 1 mmolamino acid cartridges, except for the fluorescein(6-FAM)-labeled lysine,where 1 mmol Fmoc-Lys(4-methyltrityl) was weighed into the cartridge.The N-terminal acetyl group was incorporated by putting 1 mmol aceticacid in a cartridge and coupling as described hereinabove. Selectiveremoval of the 4-methyltrityl group was accomplished with a solution of95:4:1 DCM:TIS:TFA (v/v/v) flowed through the resin over 15 minutes,followed by quenching with a flow of dimethylformamide. Single-isomer6-carboxyfluorescein-NHS was reacted with the lysine side-chain in 1%DIEA in DMF and confirmed complete by ninhydrin testing. The peptide wascleaved from the resin and side-chains deprotected by treating with80:5:5:5:2.5:2.5TFA:water:phenol:thioanisole:triisopropylsilane:3,6-dioxa-1,8-octanedithiol(v/v/v/v/v/v), and the crude peptide was recovered by precipitation withdiethyl ether. The crude peptide was purified by reverse-phasehigh-performance liquid chromatography, and its purity and identity wereconfirmed by analytical reverse-phase high-performance liquidchromatography and matrix-assisted laser-desorption mass-spectrometry(m/z=2137.1 ((M+H)⁺)).

Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) Assay

Representative compounds were serially diluted in dimethyl sulfoxide(DMSO) starting at 50 μM (2× starting concentration; 10% DMSO) and 10 μLwere transferred into a 384-well plate. Then 10 μL of aprotein/probe/antibody mix was added to each well at finalconcentrations listed in TABLE 1.

TABLE 1 Protein, Probe And Antibody Used For TR-FRET Assays Anti-Protein Probe Anti- body Protein Probe (nM) (nM) body (nM) GST-F-Bak(SEQ. ID. No. 1 100 Tb- 1 Bcl-2 1)(GQVGRQLAIIGDK anti-(6-FAM) (SEQ ID GST No. 2)INR-amide) GST- F-Bak(SEQ. ID. No. 1 100 Tb- 1Bcl-X_(L) 1)(GQVGRQLAIIGDK anti- (6-FAM) (SEQ ID GST No. 2)INR-amide)6-FAM = 6-carboxyfluorescein.; Tb = terbium; GST = glutathioneS-transferase

The samples were then mixed on a shaker for 1 minute and incubated foran additional 3 hours at room temperature. For each assay, theprobe/antibody and protein/probe/antibody were included on each assayplate as negative and positive controls, respectively. Fluorescence wasmeasured on the Envision (Perkin Elmer) using a 340/35 nm excitationfilter and 520/525 (F-Bak peptide) and 495/510 nm (Tb-labeledanti-Histidine antibody) emission filters.

Inhibition constants (K_(i)) for compounds according to the inventionand ABT-737, and the binding selectivity ratio (Bcl-X_(L) K_(i):Bcl-2K_(i)) for each are shown in TABLE 2 below. The inhibition constant(K_(i)) is the dissociation constant of an enzyme-inhibitor complex or aprotein/small molecule complex, wherein the small molecule is inhibitingbinding of one protein to another protein or peptide. Where the K_(i)for a compound is represented as “>” (greater than) a certain numericalvalue, it is intended to mean that the binding affinity value (e.g., forBcl-X_(L)) is greater than the limits of detection of the assay used.Where the binding selectivity ratio for a compound is represented as “>”(greater than) a certain numerical value, it is intended to mean thatthe selectivity of a particular compound for Bcl-2 over Bcl-X_(L) is atleast as great as the number indicated. Where the K_(i) for a compoundis represented as “<” (less than) a certain numerical value, it isintended to mean that the binding affinity value (e.g., for Bcl-2) islower than the limit of detection of the assay used. Inhibitionconstants were determined using Wang's equation (Wang Z-X., An ExactMathematical Expression For Describing Competitive Binding Of TwoDifferent Ligands To A Protein Molecule. FEBS Lett. 1995, 360:111-4).

TABLE 2 TR-FRET Binding Affinity Binding selectivity ratio Bcl-2 K_(i),Bcl-X_(L) K_(i) (Bcl-X_(L) K_(i)/Bcl-2 Example (μM) (μM) K_(i)) ABT-7370.000088 0.00008 0.9  1 0.006773 0.57833 85.4  18 0.000238 0.008131 34.2 19 0.000847 0.020027 23.6  20 0.002365 0.077593 32.8  21 0.0054280.19038 35.1  22 0.006218 0.1253 20.2  23 0.006639 0.16782 25.3  240.000194 >0.66 >3402.1  25 0.00005 0.20519 4103.8  260.00014 >0.66 >4714.3  28 0.033705 >0.66 >19.6  29 0.011911 >0.66 >55.4 30 0.10292 >0.66 >6.4  31 0.036614 >0.66 >18.0  32 0.061123 >0.66 >10.8 33 0.006684 0.33339 49.9  34 0.001986 0.088007 44.3  36 0.0007960.008995 11.3  37 0.000464 0.044422 95.7  40 0.000534 >0.66 >1236.0  420.000048 0.003841 80  45 0.000828 >0.66 >797.1  46 0.000159 0.018958119.2  47 0.00663 0.10428 15.7  50 0.000471 0.090073 191.2  51 0.0002520.015646 62.1  52 0.000239 0.079805 333.9  53 0.000081 0.004845 59.8  540.000757 0.082015 108.3  55 0.000196 0.02488 126.9  56 0.000268 0.01292448.2  57 0.000068 0.004674 68.7  58 0.001085 0.28807 265.5  59 0.0006721.255 1867.6  60 0.01893 >0.66 >34.9  61 0.05221 >0.66 >12.6  620.003516 0.5711 162.4  64 0.000523 0.040334 77.1  65 0.004558 0.0218054.8  67 0.28867 >0.66 >2.3  68 0.001227 0.013969 11.4  69 0.0012450.092074 74  70 0.001192 0.074407 62.4  71 0.006233 >0.66 >105.9  720.003022 0.052359 17.3  73 0.001697 0.016885 9.9  74 0.00002 0.0252491262.5  75 0.000125 0.10653 852.2  76 0.000051 0.003288 64.5  780.11251 >0.66 >5.9  79 0.00205 0.0972 47.4  85 0.000236 0.011521 48.8 86 0.000212 0.010522 49.6  87 0.000762 0.40679 533.8  88 0.0000690.004642 67.3  89 0.000129 0.007453 57.8  90 0.002134 0.28384 133  910.000193 0.010191 52.8  92 0.004375 0.34857 79.7  93 0.000231 0.01386160  94 0.00007 0.002317 33.1  95 0.00006 0.015699 261.7  96 0.0000470.008781 186.8  97 0.000027 0.002611 96.7  98 0.000013 >0.66 >50769.2 99 0.00004 0.00553 138.3 100 0.000116 0.008288 71.4 101 0.0000920.011152 121.2 102 0.000035 0.002242 64.1 103 0.000056 0.11738 2096.1104 0.000077 0.049106 637.7 105 0.00008 0.005016 62.7 107 0.0020870.13041 62.5 108 0.002342 0.059639 25.5 109 0.000161 >0.66 >4099.4 1140.000096 0.014325 149.2 115 0.000176 0.027527 156.4 116 0.0000360.008305 230.7 117 0.002299 >0.66 >287.1 118 0.000769 >0.66 >858.3 1190.000622 0.23029 370.2 120 0.000443 0.099593 224.8 121 0.000001 0.000388388 122 0.000058 0.012144 209.4 123 0.000015 0.001372 91.5 124 0.0003350.073725 220.1 125 0.000003 0.011637 3879 126 0.000012 0.1629 13575 1270.000459 >0.66 >1437.9 128 0.000051 0.363 7117.6 1290.000056 >0.66 >11785.7 130 0.00014 >0.66 >4714.3 131 0.000106 0.242972292.2 132 0.000553 0.31529 570.1 133 0.000009 0.000281 31.2 1340.000052 0.01805 347.1 135 0.000008 0.006239 779.9 136 0.000259 0.061863238.9 137 0.000305 0.015977 52.4 138 0.000009 0.005174 574.9 1390.000101 0.010416 103.1 140 0.004726 >0.66 >139.7 141 0.000673 0.02864242.6 142 0.003664 0.10184 27.8 143 0.002232 0.075383 33.8 1440.053902 >0.66 >12.2 145 0.00003 0.012029 401 146 0.044184 >0.66 >14.9147 0.000514 >0.66 >1284.0 148 0.00289 >0.66 >228.4 1490.000265 >0.66 >2490.6 150 0.000014 0.009338 667 1510.000162 >0.66 >4074.1 152 0.000026 0.000412 15.8 153 0.000265 0.093006351 154 0.000133 0.005375 40.4 155 0.000484 0.037667 77.8 156 0.0001160.006155 53.1 157 0.004454 >0.66 >148.2 158 0.06478 >0.66 >10.2 1610.00171 >0.66 >386.0 162 0.001348 0.16692 123.8 1630.005616 >0.66 >117.5 164 0.000963 0.13795 143.3 165 0.000823 0.03658544.5 166 0.000459 0.00327 7.1 169 0.00097 0.088637 91.4 170 0.0001260.003802 30.2 171 0.002942 0.052053 17.7 172 0.002048 0.06569 32.1 1730.000108 0.022102 204.6 174 0.000105 0.062087 591.3 1750.0001 >0.660 >6600 176 0.00018 0.032 177.8 177 0.000165 0.132 799.7 1780.000226 >0.660 >2915.8 179 0.000181 >0.660 >3642.4 1800.000192 >0.660 >3438.6 181 0.000291 >0.660 >2271.9 1820.000087 >0.660 >7595.8 183 0.000039 0.009428 240.5 1840.000281 >0.660 >2345.3 185 0.000228 0.082582 361.5 186 0.00001 0.0111991069.2 187 0.000329 >0.660 >2003.9 188 0.000102 0.11529 1135.4 1890.000144 0.051724 358.6 190 0.000512 0.097064 189.6 191 0.0000730.009162 125.2 194 0.000151 0.032029 212.4 195 0.000039 0.00671 170.2196 0.000032 >0.660 >20552.4 197 0.000025 0.004837 193 1980.003966 >0.660 >166.4 199 0.000014 0.005231 369.8 2000.0001 >0.660 >6588.8 201 0.000125 0.024585 196.6 202 0.000052 0.00507397.1 203 0.000031 0.004305 139.5 204 0.000145 0.042341 291.3 2050.000005 0.003573 658.6 206 0.000083 >0.660 >7916.4 2070.000218 >0.660 >3021.3 208 0.000589 >0.660 >1120.6 2090.000267 >0.660 >2476.0 210 0.000624 >0.660 >1057.6 211 0.0000090.005612 651.1 212 0.000737 >0.660 >895.1 213 <0.00001 >0.660 >66000 2140.000082 0.064044 776.6 215 0.000503 0.060768 120.8 2160.000615 >0.660 >1073.2 217 0.000262 0.044761 171.1 218 0.0001310.096873 738.2 219 0.000236 0.029861 126.8 220 0.000192 0.031387 163.7221 0.000057 0.1701 3005.2 222 0.000107 0.13661 1275.3 223 0.0001690.097266 574.1 224 <0.00001 0.000999 >99.9 225 0.00001 0.003482 >348.2226 0.000017 0.009928 577.7 227 0.006831 >0.660 >96.6 2280.004669 >0.660 >141.4 229 0.049413 >0.660 >13.4 2300.008819 >0.660 >74.8 231 0.000918 >0.660 >718.8 232 0.00046 0.19749429.1 233 0.000243 >0.660 >2714.3 234 0.000369 0.024503 66.3 2350.000252 0.058196 231.4 236 0.000369 >0.660 >1787.6 237 0.000401 0.268668.3 238 0.00043 >0.660 >1534.3 239 0.000252 0.10842 430.9 2400.00083 >0.660 >795.4 241 0.006091 >0.660 >108.3 2420.001796 >0.660 >367.6 243 0.00028 >0.660 >2357.6 2440.00016 >0.660 >4136.9 245 0.001617 >0.660 >408.2 246 0.000783 0.38418490.9 247 0.000188 0.027265 145.3 248 0.000013 0.15503 12079.6 2490.00009 >0.660 >7302.0 250 0.000266 0.21547 811 251 0.000328 0.471661438.5 252 0.000077 >0.660 >8570.3 253 0.000142 >0.660 >4663.3 2540.000126 0.053315 421.7 255 0.007834 >0.660 >84.2 2560.00012 >0.660 >5519.8 257 0.000171 0.017126 100.2 258 0.000048 0.00408586 259 0.001995 >0.660 >330.9 260 0.001087 >0.660 >607.2 2610.000088 >0.660 >7530.1 262 0.003001 >0.660 219.9 2630.000316 >0.660 >2090.0 264 0.000235 >0.660 >2808.4 2650.001698 >0.660 >388.8 266 0.000183 >0.660 >3607.7 2670.000454 >0.660 >1453.3 268 0.000092 0.14465 1563.9 269 nd nd nd 2700.003314 >0.660 >199.1 271 0.006156 >0.660 >107.2 2720.000011 >0.660 >58011.8 273 0.000076 0.18104 2396.1 274 0.0001350.032908 244.6 275 0.000097 >0.660 >6832.4 276 0.000144 0.38147 2650.8277 0.029684 >0.660 >22.2 278 0.00071 >0.660 >929.4 2790.000095 >0.660 >6923.2 280 0.000178 0.19477 1097.2 281 0.000076 0.119251558.9 282 0.000164 0.56153 3434.4 283 0.047464 >0.660 >13.9 2840.001552 >0.660 >425.2 285 0.006994 >0.660 >94.4 2860.000567 >0.660 >1165.0 287 nd nd nd 288 0.000177 >0.660 >3730.9 2890.000112 >0.660 >5917.7 290 0.000365 >0.660 >1808.5 2910.00056 >0.660 >1179.1 292 0.000598 >0.660 >1104.2 293 0.000516 0.2604505.1 294 0.000258 0.065126 252 295 0.000183 0.10971 599.4 2960.000651 >0.660 >1014.4 297 0.000128 0.28281 2209.5 298 0.000315 0.445931415.7 299 0.000425 0.24551 577.7 300 nd >0.660 nd 3010.000291 >0.660 >2268.0 302 0.000504 >0.660 >1309.5 3030.00148 >0.660 >445.9 304 0.000678 >0.660 >973.5 3050.003684 >0.660 >179.2 306 0.000077 0.047895 622 3070.003727 >0.660 >177.1 308 0.057376 >0.660 >11.5 3090.004417 >0.660 >149.4 310 0.000049 >0.660 >13469.4 3110.00026 >0.660 >2538.5 312 0.00034 >0.660 >1941.2 313 0.000044 0.0661500 314 0.003066 >0.660 >215.3 315 0.003461 >0.660 >190.7 316 0.0001490.079528 533.7 317 0.002798 >0.660 >235.9 318 0.001468 0.15067 102.6 3190.000413 0.20791 503.4 320 0.001243 0.12873 103.6 3210.000689 >0.660 >957.9 322 0.000184 >0.660 >3591.4 3230.000949 >0.660 >695.2 324 0.001481 >0.660 >445.7 3250.002331 >0.660 >283.1 326 0.000116 >0.660 >5708.8 327 0.000031 0.0955753035.4 328 0.001859 >0.660 >355.0 329 0.000285 >0.660 >2319.5 3300.074915 >0.660 >8.8 331 0.008266 >0.660 >79.8 332 0.012582 >0.660 >52.5333 0.000089 >0.660 >7415.7 334 0.000179 >0.660 >3697.5 3350.000438 >0.660 >1508.2 336 0.000105 0.24152 2301.3 3370.000535 >0.660 >1233.3 338 0.000403 >0.660 >1637.7 3390.014136 >0.660 >46.7 340 0.007593 >0.660 >86.9 3410.012998 >0.660 >50.8 342 0.025752 >0.660 >25.6 3430.000576 >0.660 >1145.9 344 0.000284 0.44708 1576.9 3450.001146 >0.660 >575.9 346 0.000018 0.20364 11405.2 347 0.000243 0.305561256.7 348 0.000302 0.029266 97.1 349 0.000467 0.024235 51.9 3500.00597 >0.660 >110.6 351 0.001576 >0.660 >418.7 3520.006825 >0.660 >96.7 353 0.000292 >0.660 >2260.0 354 0.000036 0.00541148.8 355 0.00012 >0.660 >5489.5 356 0.005015 >0.660 >131.6 3570.001336 >0.660 >493.9 358 0.005417 >0.660 >121.8 3590.013481 >0.660 >49.0 360 0.000228 0.14423 633.9 3610.007128 >0.660 >92.6 362 0.000082 0.28999 3548.2 3630.00018 >0.660 >3670.5 364 0.000006 0.07596 12197.3 3650.001077 >0.660 >612.9 366 0.005457 >0.660 >121.0 3670.004608 >0.660 >143.2 368 >1.195 >0.660 — 369 0.8382 >0.660 >0.8 3700.000904 >0.660 >729.9 371 0.008376 >0.660 >78.8 372 >1.195 >0.660 — 3740.002266 >0.660 >291.2 375 0.011254 >0.660 >58.6 3760.022405 >0.660 >29.5 377 0.00014 0.32457 2317.4 3780.063003 >0.660 >10.5 379 0.25595 >0.660 >2.6 380 0.000083 0.174912107.3 381 0.000054 0.024207 448.3 382 0.00115 >0.660 >573.9 3830.00217 >0.660 >304.1 384 0.000076 >0.660 >8684.2 385 0.000062 0.129982096.5 386 0.000239 0.11818 494.5 387 0.000162 0.27983 1723.4 3880.000188 0.034845 185.1 389 0.000098 0.067181 685.5 390 0.000341 0.11581339.6 391 0.00354 >0.660 >186.4 392 0.00038 0.121691 320.2394737 3930.000083 0.0921 1109.638554 394 0.002507 >660 >263262.863980854 3950.000798 0.018843 23.62136616 396 0.11567 >660 >5705.88743840235 3970.022972 >660 >28730.6285913286 398 0.001233 0.083449 67.68513261 3990.002923 >660 >225764.520763495 400 <0.00001 0.036438 >3643.8 401<0.00001 0.001621 >162.14 402 0.00003 0.004152 137.4441318 403 0.0000030.024340 8250.567777 404 0.000012 0.030268 2423.47572 405 0.0000400.055325 1394.84167 406 0.000035 0.044553 1263.771487 407 0.0000150.074556 4930.626281 408 0.000002 0.028131 13701.71935 409 <0.0000100.017485 1748.5 410 0.000055 0.101630 1838.625057 411 0.000003 0.0074532352.34518 412 0.000021 0.135210 6545.480951 413 0.000120 0.096802803.8030391 414 0.000007 0.095640 13930.52218 415 0.000002 0.02690017326.89211 416 0.000023 0.059112 2568.970013 417 0.000046 0.00398687.05823249 418 0.000004 0.001566 404.6578954 419 0.000197 0.2112401070.762368 420 0.000063 0.072108 1153.285139 421 0.000026 0.0540392089.513572 422 0.000071 0.289500 4073.448713 423 <0.000010 0.007566756.62 424 <0.000010 0.007825 782.52 425 0.000003 0.003995 1282.243051426 0.000007 0.004311 604.2384997 427 0.000002 0.085636 34408.55031 4280.000003 0.015643 5832.15271 429 <0.000010 0.001407 140.65 430 <0.0000100.000998 99.767 431 <0.000010 0.006774 677.36 432 0.000023 0.009298408.8250813 433 <0.000010 0.002286 228.55 434 0.000052 0.0754741459.393611 435 0.000017 0.032896 1935.058824 436 0.000011 0.006500590.9090909 437 <0.000010 0.000514 51.4 438 <0.000010 0.000345 34.5 439<0.000010 0.014968 1496.8 440 <0.000010 0.045491 4549.1 441 <0.0000100.024219 2421.9 442 <0.000010 0.033589 3358.9 443 <0.000010 0.0193571935.7 444 0.000112 0.081494 727.625 445 0.000028 0.013557 484.1785714446 0.000038 0.019318 508.3684211 447 0.000028 0.065838 2373.053633 4480.000005 0.014610 3119.262138 449 0.000240 0.017841 74.40260228 4500.000299 0.032065 107.2874494 451 <0.000010 0.003599 359.92 452<0.000010 0.006004 600.39 453 <0.000010 0.003630 363.04 454 0.0000260.018906 735.2415027 455 0.000004 0.000619 139.3622053 456 <0.0000100.000540 53.991 457 0.000045 0.330930 7413.638604 458 <0.000010 0.002372237.24 459 <0.000010 0.005416 541.58 460 0.000049 0.028982 586.5495537461 0.000093 0.003650 39.43935939 462 0.000026 0.018425 710.8410494 4630.000007 0.043884 6042.880159 464 0.000081 0.521110 6431.789289 4650.000025 0.037216 1472.443126 467 0.000080 0.13291 1653.027213 4730.079276 0.19124 2.412331601 nd = not determined

TABLE 2 shows the utility of compounds having Formula I to functionallyinhibit anti-apoptotic Bcl-2 protein. It also surprisingly demonstratesthese compounds having comparatively less affinity for anti-apoptoticBcl-xL protein, which in turn gives rise to high binding selectivityratios (Bcl-xL K_(i)/Bcl-2 K_(i)) ranging from >2 to >263, 263. Thisselectivity for Bcl-2 protein is significantly greater than compoundspreviously disclosed in PCT US 2004/36770 and PCT US 2004/367911, asexemplified by ABT-737 in TABLE 2.

For some compounds (e.g., 192 and 193), the assay did not detect anyactivity against either Bcl-2 or Bcl-XL under the conditions statedabove in the experimental description for the FRET assay. As thoseskilled in the art will appreciate, the upper and lower limits ofdetection in an assay are influenced by the assay conditions, and forthe FRET assay specifically, by the concentration of the probe that isused. Since compounds represented by Examples 192 and 193 show K_(i)values that are greater than the limits of detection in the assay formatused, it can be stated that their affinity for Bcl-2 and Bcl-XL is lessthan the upper limit of detection of the assays. However, they may stillhave affinity for one or both proteins, and the inventors expect thatthey also have selectivity for Bcl-2.

Platelet Cell Viability Assay

Platelet-rich plasma (PRP) (prepared in-house according to conventionaltechniques) was incubated with ABT-737(4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide)or compounds of the invention at various concentrations for five hoursat 37° C. After the incubation, platelets were equilibrated to roomtemperature for 20 minutes and then an equal volume of Cell Titer Gloreagent (Promega Corporation) was added. Samples were mixed for twominutes and then allowed to equilibrate for an additional 10 minutes atroom temperature. The luminescence generated from the samples wasquantitated using an LJL Analyst plate reader. IC₅₀ values areconcentrations of compound needed for 50% inhibition of cellularviability.

FL5.12/Bcl-2 Cell Viability Assay

FL5.12 is an IL-3 dependent prolymphocytic murine cell line thatundergoes apoptosis upon IL-3 withdrawal as a result of the upregulationof pro-apoptotic Bcl-2 proteins such as Bim and Puma. Stableoverexpression of anti-apoptotic Bcl-2 protein (FL5.12/Bcl-2) protectsagainst apoptosis induced by IL-3 withdrawal by sequestration of Bim andPuma. [Refs. Harada, et. al. PNAS 101, 15313 (2004); Certo, et. al.Cancer Cell 9, 351 (2006).] The ability of compounds to killFL5.12/Bcl-2 cells upon IL-3 withdrawal is a direct measure of thecompounds' ability to inhibit anti-apoptotic Bcl-2 protein function.

Wild type FL5.12/Bcl-2 overexpressing stable transfectants were culturedin RPMI-1640 supplemented with 2 mM L-glutamine, 10% FBS, 1 mM sodiumpyruvate, 2 mM HEPES, 1% penicillin/streptomycin (Invitrogen), 57 μM(3-ME, and 10% WEHI-3B conditioned medium (source of IL-3) andmaintained at 37° C. containing 5% CO₂. 1×10⁶ cells/ml were washed 1×PBSand resuspended in medium not supplemented with 10% WEHI-3B for 48 hrsprior to cytotoxicity assays. Cells were then treated for an additional24 hrs in the presence of various concentrations of the indicatedcompounds. Cell viability was assessed by CellTitre Glo assay (PromegaCorp.) according to the manufacturer's recommendations.

Data analysis was performed using GraphPad Prism 4.0 and results areshown in TABLE 3 below.

TABLE 3 Cellular Activity Selectivity Canine Ratio platelets (PlateletEC₅₀/FL5.12/ FL5.12/Bcl-2 EC₅₀ Bcl-2 EC₅₀ (μM) (μM) EC₅₀) ABT- 0.0250.282 11 737  18 0.123 29.69 241  21 1.01 >50 >49  22 0.825 >50 >61  231.44 >50 >35  24 0.055 >50 >906  25 0.049 >50 >1020  26 0.035 >50 >1429 40 0.165 >50 >303  45 0.139 >50 >360  46 0.041 30 725  520.016 >50 >3164  53 0.011 18.325 1697  54 0.064 >50 >785  55 0.022 361614  56 0.049 27 554  57 0.016 16.8 1077  68 0.044 >50 >1144  690.075 >50 >666  70 0.111 >50 >450  71 0.46 >50 >107  72 0.154 >50 >325 73 0.14 23.22 166  74 0.008 16.71 1989  75 0.022 17.73 821  76 0.0398.66 221  86 0.074 36.27 489  88 0.032 19.87 613  89 0.065 31.95 495  940.04 23.85 590  96 0.011 22.27 2043  97 0.013 14.1 1052  98 0.004 17.944849  99 0.009 21.72 2440 100 0.015 31.25 2029 102 0.02 20.21 996 1030.014 31.35 2305 104 0.021 >50 >2392 105 0.013 30.31 2262 106 0.00915.24 1657 109 0.036 >50 >1404 120 0.319 >50 >157 121 0.038 0.309 8 1220.04 >50 >1259 123 0.087 2.81 32 125 0.01 44.83 4719 126 0.031 >50 >1618128 0.025 >50 >2000 129 0.021 >50 >2415 130 0.197 >50 >254 1310.031 >50 >1597 132 0.042 >50 >1196 133 0.02 0.095 5 134 0.048 4.72 98135 0.042 4.55 108 136 0.19 >50 >263 137 0.281 >50 >178 138 0.029 17.75616 139 0.046 38.5 841 140 2.13 >50 >23 141 0.076 >50 >661 1420.27 >50 >185 143 0.199 >50 >251 144 0.046 40.02 864 145 0.004 3.21 730146 0.152 21.97 145 147 0.009 17.62 1895 148 0.071 19.77 278 149 0.01316.74 1298 150 0.006 2.9 509 151 0.049 31.4 642 152 0.009 2.66 283 1540.085 29 343 155 0.421 >50 >119 166 0.153 >50 >327 170 0.015 7.35 507171 0.276 >50 >181 172 0.194 >50 >257 173 0.011 >50 >4587 174 0.011 19.51857 175 0.0062 nd nd 176 0.0585 nd nd 177 0.01966 nd nd 178 0.0186 ndnd 179 0.02346 nd nd 180 0.02047 nd nd 181 0.03353 nd nd 182 0.01242 ndnd 183 0.03077 nd nd 184 0.02698 nd nd 185 0.06335 nd nd 186 0.02036 ndnd 187 0.34128 nd nd 188 0.02466 nd nd 189 0.01489 nd nd 190 0.02421 ndnd 191 0.01172 nd nd 192 >0.5 nd nd 193 >0.5 nd nd 194 0.02697 nd nd 1950.01124 nd nd 196 0.01236 nd nd 197 0.00618 nd nd 198 nd nd nd 1990.02854 nd nd 200 0.00629 nd nd 201 0.0174 nd nd 202 0.01383 nd nd 2030.0223 nd nd 204 0.02738 nd nd 205 0.03753 nd nd 206 0.00501 nd nd 2070.1199 nd nd 208 0.26403 nd nd 209 0.13896 nd nd 210 0.25691 nd nd 2110.01713 nd nd 212 >0.5 nd nd 213 0.43216 nd nd 214 0.01569 nd nd 2150.11576 nd nd 216 0.03985 nd nd 217 0.02083 nd nd 218 0.033 nd nd 2190.02296 nd nd 220 0.02403 nd nd 221 0.14872 nd nd 222 0.02366 nd nd 2230.03713 nd nd 224 0.02116 nd nd 225 0.02989 nd nd 226 0.02301 nd nd227 >0.5 nd nd 228 >0.5 nd nd 229 >0.5 nd nd 230 0.17755 nd nd 2310.0509 nd nd 232 0.01228 nd nd 233 nd nd nd 234 nd nd nd 235 nd nd nd236 nd nd nd 237 nd nd nd 238 0.05896 nd nd 239 0.01764 nd nd 2400.20943 nd nd 241 nd nd nd 242 0.16457 nd nd 243 0.028 nd nd 244 0.02025nd nd 245 0.07244 nd nd 246 0.048 nd nd 247 0.01607 nd nd 248 0.04981 ndnd 249 0.0412 nd nd 250 0.07951 nd nd 251 0.07812 nd nd 252 0.00662 ndnd 253 0.00758 nd nd 254 0.01693 nd nd 255 >0.5 nd nd 256 0.00889 nd nd257 0.00934 nd nd 258 0.00911 nd nd 259 >0.5 nd nd 260 0.05944 nd nd 2610.01701 nd nd 262 0.17622 nd nd 263 0.02835 nd nd 264 0.02571 nd nd 2650.24417 nd nd 266 0.01148 nd nd 267 0.05643 nd nd 268 0.06822 nd nd 269nd nd nd 270 0.42893 nd nd 271 >0.5 nd nd 272 0.19406 nd nd 273 0.07001nd nd 274 0.15519 nd nd 275 0.03801 nd nd 276 0.06218 nd nd 277 >0.5 ndnd 278 0.15272 nd nd 279 0.01623 nd nd 280 0.24715 nd nd 281 0.06022 ndnd 282 0.09216 nd nd 283 >0.5 nd nd 284 >0.5 nd nd 285 >0.5 nd nd 2860.27896 nd nd 287 nd nd nd 288 0.06432 nd nd 289 0.02736 nd nd 2900.04468 nd nd 291 0.05801 nd nd 292 0.06916 nd nd 293 0.06806 nd nd 2940.05981 nd nd 295 0.04634 nd nd 296 0.18237 nd nd 297 0.01321 nd nd 2980.01948 nd nd 299 0.07725 nd nd 300 0.06215 nd nd 301 0.05945 nd nd 3020.03238 nd nd 303 >0.5 nd nd 304 0.41529 nd nd 305 >0.5 nd nd 3060.00716 nd nd 307 >0.5 nd nd 308 >0.5 nd nd 309 >0.5 nd nd 310 0.00451nd nd 311 0.0334 nd nd 312 0.01924 nd nd 313 0.08289 nd nd 314 0.24014nd nd 315 >0.5 nd nd 316 0.06749 nd nd 317 0.08309 nd nd 318 0.07695 ndnd 319 0.03141 nd nd 320 0.04158 nd nd 321 0.02909 nd nd 322 0.04445 ndnd 323 0.09208 nd nd 324 0.13417 nd nd 325 0.25639 nd nd 326 0.03509 ndnd 327 0.00657 nd nd 328 >0.5 nd nd 329 0.12652 nd nd 330 >0.5 nd nd331 >0.5 nd nd 332 >0.5 nd nd 333 0.10932 nd nd 334 0.06592 nd nd 3350.03897 nd nd 336 0.00749 nd nd 337 0.12389 nd nd 338 0.07113 nd nd339 >0.5 nd nd 340 >0.5 nd nd 341 >0.5 nd nd 342 >0.5 nd nd 343 0.05489nd nd 344 0.07147 nd nd 345 >0.5 nd nd 346 0.01747 nd nd 347 0.04681 ndnd 348 0.0872 nd nd 349 0.14571 nd nd 350 0.31119 nd nd 351 0.34452 ndnd 352 0.15632 nd nd 353 0.05828 nd nd 354 0.0056 nd nd 355 >0.5 nd nd356 >0.5 nd nd 357 >0.5 nd nd 358 >0.5 nd nd 359 >0.5 nd nd 360 0.10622nd nd 361 >0.5 nd nd 362 0.17126 nd nd 363 0.08692 nd nd 364 0.18474 ndnd 365 >0.5 nd nd 366 >0.5 nd nd 367 >0.5 nd nd 368 >0.5 nd nd 369 >0.5nd nd 370 0.26334 nd nd 371 >0.5 nd nd 372 >0.5 nd nd 374 >0.5 nd nd375 >0.5 nd nd 376 >0.5 nd nd 377 0.08573 nd nd 378 >0.5 nd nd 379 >0.5nd nd 380 0.06849 nd nd 381 0.07185 nd nd 382 >0.5 nd nd 383 >0.5 nd nd384 0.10121 nd nd 385 0.05636 nd nd 386 0.15353 nd nd 387 0.08652 nd nd388 0.08288 nd nd 389 0.02812 nd nd 390 0.04118 nd nd 391 >0.5 nd nd 392nd nd nd 393 nd nd nd 394 nd nd nd 395 nd nd nd 396 >0.5 nd nd 397 nd ndnd 398 0.33382 nd nd 399 >0.5 nd nd 400 0.00847 nd nd 401 0.00538 nd nd402 0.01336 nd nd 403 0.00292 nd nd 404 0.00234 nd nd 405 0.01162 nd nd406 0.02046 nd nd 407 0.0081 nd nd 408 0.00239 nd nd 409 0.0012 nd nd410 0.01386 nd nd 411 0.01145 nd nd 412 0.00948 nd nd nd = notdetermined

TABLE 3 shows the utility of compounds having Formula I to functionallyinhibit anti-apoptotic Bcl-2 protein in a cellular context. FL5.12 is anIL-3 dependent prolymphocytic murine cell line that undergoes apoptosisupon IL-3 withdrawal as a result of the upregulation of pro-apoptoticBcl-2 family proteins such as Bim and Puma. Stable overexpression ofanti-apoptotic Bcl-2 protein (FL5.12/Bcl-2) protects against apoptosisinduced by IL-3 withdrawal by sequestration of Bim and Puma. (Refs.Harada, et. al. PNAS 2004, 101, 15313; Certo, et. al. Cancer Cell 2006,9, 351.) The ability of compounds to kill FL5.12/Bcl-2 cells upon IL-3withdrawal is a direct measure of the compounds ability to inhibitanti-apoptotic Bcl-2 protein function. Compounds of Formula I are veryeffective in killing FL5.12/Bcl-2 cells under IL-3 withdrawal asdemonstrated by low EC₅₀ values.

Compounds of this invention bind to anti-apoptotic Bcl-2 proteins withhigh affinity and potently inhibit the function of anti-apoptotic Bcl-2protein in a cellular context and are therefore expected to have utilityin treatment of diseases during which anti-apoptotic Bcl-2 protein isexpressed.

The anti-apoptotic Bcl-xL protein has been disclosed elsewhere (CellMar. 23, 2007, 128, 1173-1176.) to be the major regulator of thesurvival of circulating platelets in animals. Genetic mutations toBcl-xL protein that decrease Bcl-xL protein stability and half-lifecauses a decrease in platelet survival and life-span in mice bearingthese mutations. A potent pharmacologic inhibitor of Bcl-xL, ABT-737,causes a rapid, concentration dependant decrease in circulatingplatelets following injection into C57BL/6 mice or in beagle canines(Cell Mar. 23, 2007, 128, 1173-1176.; Cell Death Differ. May 2007;14(5), 943-51). Thus, without being limited by theory, compounds of thisinvention that have reduced affinity for Bcl-xL can be expected to showlower levels of platelet apoptosis than previously reported compoundswith higher Bcl-xL affinity.

The effect of compounds on platelet survival can be directly evaluatedex vivo by examining the viability of isolated canine platelets in thepresence of various concentrations of compound. The data in Table 3shows that compounds of Formula I have significantly less to no effecton the viability of isolated canine platelets ex vivo (higher EC₅₀values) compared to compounds previously disclosed in PCT US 2004/36770and PCT US 2004/367911, as exemplified by ABT-737. Furthermore, thefunctional selectivity ratio (canine platelet EC₅₀:FL5.12/Bcl-2 EC₅₀)for compounds of Formula I ranges from 32 to 4849, which issignificantly higher than that for compounds previously disclosed in PCTUS 2004/36770 and PCT US 2004/367911, as exemplified by ABT-737.

Because compounds having Formula I bind to anti-apoptotic Bcl-2 proteinwith comparatively lower binding to anti-apoptotic Bcl-X_(L) protein,the compounds would have utility as medicaments for the treatment ofcancer and autoimmune and immune diseases with reduction of the sideeffect of thrombocytopenia (i.e., they would be circulatingplatelet-sparing). Involvement of Bcl-X_(L) in thrombocytopenia isdisclosed in Cell Mar. 23, 2007, 128, 1173-1176. As described herein andelsewhere, a potent inhibitor of Bcl-X_(L), ABT-737, causes adose-dependent decrease in circulating platelets following injectioninto C57BL/6 mice or in canines (Cell Death Differ. May 2007; 14(5),943-51). Compounds with reduced Bcl-X_(L) affinity exhibit substantiallyless to no decrease in circulating platelets. Thus, without beinglimited by theory, compounds of this invention that have reducedaffinity for Bcl-X_(L) can be expected to show lower levels of plateletapoptosis than previously reported compounds with higher Bcl-X_(L)affinity. The EC₅₀ data in TABLE 2 show the effects of administration ofcompounds of this invention, compared to ABT-737, on canine platelets.

Involvement of Bcl-2 protein in bladder cancer, brain cancer, breastcancer, bone marrow cancer, cervical cancer, chronic lymphocyticleukemia, colorectal cancer, esophageal cancer, hepatocellular cancer,lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies ofT-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oralcancer, ovarian cancer, non-small cell lung cancer, prostate cancer,small cell lung cancer, chronic lymphocytic leukemia, myeloma, prostatecancer spleen cancer, and the like is described in commonly-owned PCT US2004/36770, published as WO 2005/049593, and PCT US 2004/37911,published as WO 2005/024636.

Involvement of Bcl-2 proteins in immune and autoimmune diseases isdescribed in Current Allergy and Asthma Reports 2003, 3, 378-384;British Journal of Haematology 2000, 110(3), 584-90; Blood 2000, 95(4),1283-92; and New England Journal of Medicine 2004, 351(14), 1409-1418.

Involvement of Bcl-2 protein in arthritis is disclosed in commonly-ownedU.S. Provisional Patent Application Ser. No. 60/988,479.

Involvement of Bcl-2 protein in bone marrow transplant rejection isdisclosed in commonly-owned U.S. patent application Ser. No. 11/941,196(now U.S. Published Application 20080182845A1).

Overexpression of Bcl-2 protein correlates with resistance tochemotherapy, clinical outcome, disease progression, overall prognosisor a combination thereof in various cancers and disorders of the immunesystem. Cancers include, but are not limited to, hematologic and solidtumor types such as acoustic neuroma, acute leukemia, acutelymphoblastic leukemia, acute myelogenous leukemia (monocytic,myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocyticand promyelocytic), acute t-cell leukemia, basal cell carcinoma, bileduct carcinoma, bladder cancer, brain cancer, breast cancer (includingestrogen-receptor positive breast cancer), bronchogenic carcinoma,Burkitt's lymphoma, cervical cancer, chondrosarcoma, chordoma,choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronicmyelocytic (granulocytic) leukemia, chronic myelogenous leukemia, coloncancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma,dysproliferative changes (dysplasias and metaplasias), embryonalcarcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelialcarcinoma, erythroleukemia, esophageal cancer, estrogen-receptorpositive breast cancer, essential thrombocythemia, Ewing's tumor,fibrosarcoma, gastric carcinoma, germ cell testicular cancer,gestational trophoblastic disease, glioblastoma, head and neck cancer,heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer,hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lungcancer (including small cell lung cancer and non-small cell lungcancer), lymphangioendothelio-sarcoma, lymphangiosarcoma, lymphoblasticleukemia, lymphoma (lymphoma, including diffuse large B-cell lymphoma,follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma),malignancies and hyperproliferative disorders of the bladder, breast,colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoidmalignancies of T-cell or B-cell origin, leukemia, medullary carcinoma,medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma,myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma,oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer,pancreatic cancer, papillary adenocarcinomas, papillary carcinoma,peripheral T-cell lymphoma, pinealoma, polycythemia vera, prostatecancer (including hormone-insensitive (refractory) prostate cancer),rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma,sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small celllung carcinoma, solid tumors (carcinomas and sarcomas), stomach cancer,squamous cell carcinoma, synovioma, sweat gland carcinoma, testicularcancer (including germ cell testicular cancer), thyroid cancer,Waldenström's macroglobulinemia, testicular tumors, uterine cancer,Wilms' tumor and the like.

It is also expected that compounds having Formula I would inhibit growthof cells expressing Bcl-2 protein derived from a pediatric cancer orneoplasm including embryonal rhabdomyosarcoma, pediatric acutelymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatricalveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatricanaplastic large cell lymphoma, pediatric anaplastic medulloblastoma,pediatric atypical teratoid/rhabdoid tumor of the central nervoussystem, pediatric biphenotypic acute leukemia, pediatric Burkittslymphoma, pediatric cancers of Ewing's family of tumors such asprimitive neuroectodermal rumors, pediatric diffuse anaplastic Wilm'stumor, pediatric favorable histology Wilm's tumor, pediatricglioblastoma, pediatric medulloblastoma, pediatric neuroblastoma,pediatric neuroblastoma-derived myelocytomatosis, pediatric pre-B-cellcancers (such as leukemia), pediatric psteosarcoma, pediatric rhabdoidkidney tumor, pediatric rhabdomyosarcoma, and pediatric T-cell cancerssuch as lymphoma and skin cancer and the like.

Autoimmune disorders include acquired immunodeficiency disease syndrome(AIDS), autoimmune lymphoproliferative syndrome, hemolytic anemia,inflammatory diseases, and thrombocytopenia, acute or chronic immunedisease associated with organ transplantation, Addison's disease,allergic diseases, alopecia, alopecia greata, atheromatousdisease/arteriosclerosis, atherosclerosis, arthritis (includingosteoarthritis, juvenile chronic arthritis, septic arthritis, Lymearthritis, psoriatic arthritis and reactive arthritis), autoimmunebullous disease, abetalipoprotemia, acquired immunodeficiency-relateddiseases, acute immune disease associated with organ transplantation,acquired acrocyanosis, acute and chronic parasitic or infectiousprocesses, acute pancreatitis, acute renal failure, acute rheumaticfever, acute transverse myelitis, adenocarcinomas, aerial ectopic beats,adult (acute) respiratory distress syndrome, AIDS dementia complex,alcoholic cirrhosis, alcohol-induced liver injury, alcohol-inducedhepatitis, allergic conjunctivitis, allergic contact dermatitis,allergic rhinitis, allergy and asthma, allograft rejection,alpha-1-antitrypsin deficiency, Alzheimer's disease, amyotrophic lateralsclerosis, anemia, angina pectoris, ankylosing spondylitis associatedlung disease, anterior horn cell degeneration, antibody mediatedcytotoxicity, antiphospholipid syndrome, anti-receptor hypersensitivityreactions, aortic and peripheral aneurysms, aortic dissection, arterialhypertension, arteriosclerosis, arteriovenous fistula, arthropathy,asthenia, asthma, ataxia, atopic allergy, atrial fibrillation (sustainedor paroxysmal), atrial flutter, atrioventricular block, atrophicautoimmune hypothyroidism, autoimmune haemolytic anaemia, autoimmunehepatitis, type-1 autoimmune hepatitis (classical autoimmune or lupoidhepatitis), autoimmune mediated hypoglycaemia, autoimmune neutropaenia,autoimmune thrombocytopaenia, autoimmune thyroid disease, B celllymphoma, bone graft rejection, bone marrow transplant (BMT) rejection,bronchiolitis obliterans, bundle branch block, burns, cachexia, cardiacarrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy,cardiopulmonary bypass inflammation response, cartilage transplantrejection, cerebellar cortical degenerations, cerebellar disorders,chaotic or multifocal atrial tachycardia, chemotherapy associateddisorders, chlamydia, choleosatatis, chronic alcoholism, chronic activehepatitis, chronic fatigue syndrome, chronic immune disease associatedwith organ transplantation, chronic eosinophilic pneumonia, chronicinflammatory pathologies, chronic mucocutaneous candidiasis, chronicobstructive pulmonary disease (COPD), chronic salicylate intoxication,colorectal common varied immunodeficiency (common variablehypogammaglobulinaemia), conjunctivitis, connective tissue diseaseassociated interstitial lung disease, contact dermatitis, Coombspositive haemolytic anaemia, cor pulmonale, Creutzfeldt-Jakob disease,cryptogenic autoimmune hepatitis, cryptogenic fibrosing alveolitis,culture negative sepsis, cystic fibrosis, cytokine therapy associateddisorders, Crohn's disease, dementia pugilistica, demyelinatingdiseases, dengue hemorrhagic fever, dermatitis, dermatitis scleroderma,dermatologic conditions, dermatomyositis/polymyositis associated lungdisease, diabetes, diabetic arteriosclerotic disease, diabetes mellitus,Diffuse Lewy body disease, dilated cardiomyopathy, dilated congestivecardiomyopathy, discoid lupus erythematosus, disorders of the basalganglia, disseminated intravascular coagulation, Down's Syndrome inmiddle age, drug-induced interstitial lung disease, drug-inducedhepatitis, drug-induced movement disorders induced by drugs which blockCNS dopamine, receptors, drug sensitivity, eczema, encephalomyelitis,endocarditis, endocrinopathy, enteropathic synovitis, epiglottitis,Epstein-Barr virus infection, erythromelalgia, extrapyramidal andcerebellar disorders, familial hematophagocytic lymphohistiocytosis,fetal thymus implant rejection, Friedreich's ataxia, functionalperipheral arterial disorders, female infertility, fibrosis, fibroticlung disease, fungal sepsis, gas gangrene, gastric ulcer, giant cellarteritis, glomerular nephritis, glomerulonephritides, Goodpasture'ssyndrome, goitrous autoimmune hypothyroidism (Hashimoto's disease),gouty arthritis, graft rejection of any organ or tissue, graft versushost disease, gram negative sepsis, gram positive sepsis, granulomas dueto intracellular organisms, group B streptococci (GBS) infection,Grave's disease, haemosiderosis associated lung disease, hairy cellleukemia, hairy cell leukemia, Hallerrorden-Spatz disease, Hashimoto'sthyroiditis, hay fever, heart transplant rejection, hemachromatosis,hematopoietic malignancies (leukemia and lymphoma), hemolytic anemia,hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura,hemorrhage, Henoch-Schoenlein purpurea, Hepatitis A, Hepatitis B,Hepatitis C, HIV infection/HIV neuropathy, Hodgkin's disease,hypoparathyroidism, Huntington's chorea, hyperkinetic movementdisorders, hypersensitivity reactions, hypersensitivity pneumonitis,hyperthyroidism, hypokinetic movement disorders,hypothalamic-pituitary-adrenal axis evaluation, idiopathic Addison'sdisease, idiopathic leucopaenia, idiopathic pulmonary fibrosis,idiopathic thrombocytopaenia, idiosyncratic liver disease, infantilespinal muscular atrophy, infectious diseases, inflammation of the aorta,inflammatory bowel disease, insulin dependent diabetes mellitus,interstitial pneumonitis, iridocyclitis/uveitis/optic neuritis,ischemia-reperfusion injury, ischemic stroke, juvenile perniciousanaemia, juvenile rheumatoid arthritis, juvenile spinal muscularatrophy, Kaposi's sarcoma, Kawasaki's disease, kidney transplantrejection, legionella, leishmaniasis, leprosy, lesions of thecorticospinal system, linear IgA disease, lipidema, liver transplantrejection, Lyme disease, lymphederma, lymphocytic infiltrative lungdisease, malaria, male infertility idiopathic or NOS, malignanthistiocytosis, malignant melanoma, meningitis, meningococcemia,microscopic vasculitis of the kidneys, migraine headache, mitochondrialmulti-system disorder, mixed connective tissue disease, mixed connectivetissue disease associated lung disease, monoclonal gammopathy, multiplemyeloma, multiple systems degenerations (Mencel Dejerine-ThomasShi-Drager and Machado-Joseph), myalgic encephalitis/Royal Free Disease,myasthenia gravis, microscopic vasculitis of the kidneys, mycobacteriumavium intracellulare, mycobacterium tuberculosis, myelodyplasticsyndrome, myocardial infarction, myocardial ischemic disorders,nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis,nephrosis, nephrotic syndrome, neurodegenerative diseases, neurogenic Imuscular atrophies, neutropenic fever, Non-alcoholic Steatohepatitis,occlusion of the abdominal aorta and its branches, occlusive arterialdisorders, organ transplant rejection, orchitis/epidydimitis,orchitis/vasectomy reversal procedures, organomegaly, osteoarthrosis,osteoporosis, ovarian failure, pancreas transplant rejection, parasiticdiseases, parathyroid transplant rejection, Parkinson's disease, pelvicinflammatory disease, pemphigus vulgaris, pemphigus foliaceus,pemphigoid, perennial rhinitis, pericardial disease, peripheralatherlosclerotic disease, peripheral vascular disorders, peritonitis,pernicious anemia, phacogenic uveitis, pneumocystis carinii pneumonia,pneumonia, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy,monoclonal gammopathy, and skin changes syndrome), post perfusionsyndrome, post pump syndrome, post-MI cardiotomy syndrome,postinfectious interstitial lung disease, premature ovarian failure,primary biliary cirrhosis, primary sclerosing hepatitis, primarymyxoedema, primary pulmonary hypertension, primary sclerosingcholangitis, primary vasculitis, Progressive supranucleo Palsy,psoriasis, psoriasis type 1, psoriasis type 2, psoriatic arthropathy,pulmonary hypertension secondary to connective tissue disease, pulmonarymanifestation of polyarteritis nodosa, post-inflammatory interstitiallung disease, radiation fibrosis, radiation therapy, Raynaud'sphenomenon and disease, Refsum's disease, regular narrow QRStachycardia, Reiter's disease, renal disease NOS, renovascularhypertension, reperfusion injury, restrictive cardiomyopathy, rheumatoidarthritis associated interstitial lung disease, rheumatoid spondylitis,sarcoidosis, Schmidt's syndrome, scleroderma, senile chorea, SenileDementia of Lewy body type, sepsis syndrome, septic shock, seronegativearthropathies, shock, sickle cell anemia, Sjögren's disease associatedlung disease, Sjörgren's syndrome, skin allograft rejection, skinchanges syndrome, small bowel transplant rejection, sperm autoimmunity,multiple sclerosis (all subtypes), spinal ataxia, spinocerebellardegenerations, spondyloarthropathy, sporadic, polyglandular deficiencytype I sporadic, polyglandular deficiency type II, Still's disease,streptococcal myositis, stroke, structural lesions of the cerebellum,Subacute sclerosing panencephalitis, sympathetic ophthalmia, Syncope,syphilis of the cardiovascular system, systemic anaphylaxis, systemicinflammatory response syndrome, systemic onset juvenile rheumatoidarthritis, systemic lupus erythematosus, systemic lupuserythematosus-associated lung disease, systemic sclerosis, systemicsclerosis-associated interstitial lung disease, T-cell or FAB ALL,Takayasu's disease/arteritis, Telangiectasia, Th2 Type and Th1 Typemediated diseases, thromboangitis obliterans, thrombocytopenia,thyroiditis, toxicity, toxic shock syndrome, transplants,trauma/hemorrhage, type-2 autoimmune hepatitis (anti-LKM antibodyhepatitis), type B insulin resistance with acanthosis nigricans, typeIII hypersensitivity reactions, type IV hypersensitivity, ulcerativecolitic arthropathy, ulcerative colitis, unstable angina, uremia,urosepsis, urticaria, uveitis, valvular heart diseases, varicose veins,vasculitis, vasculitic diffuse lung disease, venous diseases, venousthrombosis, ventricular fibrillation, vitiligo acute liver disease,viral and fungal infections, vital encephalitis/aseptic meningitis,vital-associated hemaphagocytic syndrome, Wegener's granulomatosis,Wernicke-Korsakoff syndrome, Wilson's disease, xenograft rejection ofany organ or tissue, yersinia and salmonella-associated arthropathy andthe like.

Schemes and Experimentals

The following schemes are presented to provide what is believed to bethe most useful and readily understood description of procedures andconceptual aspects of this invention. Compounds of this invention may bemade by synthetic chemical processes, examples of which are shownherein. It is meant to be understood that the order of the steps in theprocesses may be varied, that reagents, solvents and reaction conditionsmay be substituted for those specifically mentioned, and that vulnerablemoieties may be protected and deprotected, as necessary.

The following abbreviations have the meanings indicated. ADDP means1,1′-(azodicarbonyl)dipiperidine; AD-mix-β means a mixture of(DHQD)₂PHAL, K₃Fe(CN)₆, K₂CO₃, and K₂SO₄); 9-BBN means9-borabicyclo(3.3.1)nonane; Boc means tert-butoxycarbonyl; (DHQD)₂PHALmeans hydroquinidine 1,4-phthalazinediyl diethyl ether; DBU means1,8-diazabicyclo(5.4.0)undec-7-ene; DIBAL means diisobutylaluminumhydride; DIEA means diisopropylethylamine; DMAP meansN,N-dimethylaminopyridine; DMF means N,N-dimethylformamide; dmpe means1,2-bis(dimethylphosphino)ethane; DMSO means DMSO; dppb means1,4-bis(diphenylphosphino)-butane; dppe means1,2-bis(diphenylphosphino)ethane; dppf means1,1′-bis(diphenylphosphino)ferrocene; dppm means1,1-bis(diphenylphosphino)methane; EDAC.HCl means1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Fmoc meansfluorenylmethoxycarbonyl; HATU meansO-(7-azabenzotriazol-1-yl)-N,N′N′N′-tetramethyluroniumhexafluorophosphate; HMPA means hexamethylphosphoramide; IPA meansisopropyl alcohol; MP-BH₃ means macroporous triethylammoniummethylpolystyrene cyanoborohydride; TEA means triethylamine; TFA meanstrifluoroacetic acid; THF means tetrahydrofuran; NCS meansN-chlorosuccinimide; NMM means N-methylmorpholine; NMP meansN-methylpyrrolidine; PPh₃ means triphenylphosphine.

Compounds of Formula (4) can be prepared as shown in SCHEME 1, and canbe used as described in SCHEME 7 to prepare compounds of Formula (I),which are representative of the compounds of the present invention.Compounds of Formula (I) wherein R is alkyl, R¹⁰⁰ is as described forsubstituents on R²⁶, and n is 1, 2, or 3; can be converted to compoundsof Formula (2) using R³⁷CH²MgX¹, wherein X¹ is a halide, in a solventsuch as but not limited to ether or tetrahydrofuran. Compounds ofFormula (3) can be prepared from compounds of Formula (2) using a strongbase such as NaH and R⁵⁰X², wherein X² is a halide and R^(50a) is asdescribed herein. Compounds of Formula (3), when treated with aqueousNaOH or LiOH, will provide compounds of Formula (4).

As shown in SCHEME 2, compounds of Formula (5) can be reacted withcompounds of Formula (6) and a reducing agent to provide compounds ofFormula (7). Examples of reducing agents include sodium borohydride,sodium cyanoborohydride, sodium triacetoxyborohydride, polymer supportedcyanoborohydride, and the like. The reaction is typically performed in asolvent such as but not limited to methanol, tetrahydrofuran, anddichloromethane or mixtures thereof. Compounds of Formula (8) can beprepared from compounds of Formula (7) as described in SCHEME 1, and canbe used as described in SCHEME 7 to prepare compounds of Formula (I).

Compounds of Formula (9), when reacted with a compound a Formula (10)wherein X is a halide or triflate, and a base will provide a compound ofFormula (11). Bases useful in the reaction include triethylamine,diisopropylethylamine and the like. Compounds of Formula (13), whereinR⁴¹ is as described herein for substituents on R³⁷, can be prepared fromcompounds of Formula (11) and compounds of Formula (12) using Suzukicoupling conditions known to those skilled in the art and readilyavailable in the literature. Compounds of Formula (14) can be preparedfrom compounds of Formula (13) as described in SCHEME 1, and can be usedas described in SCHEME 7 to prepare compounds of Formula (I).

As shown in SCHEME 4, compounds of Formula (17) can be prepared fromcompounds of Formula (15) and compounds of Formula (16), wherein R isalkyl and R⁴¹ is as described herein, using Suzuki coupling conditionsknown to those skilled in the art and readily available in theliterature. Compounds of Formula (17) can be reduced to compounds ofFormula (18) using a reducing agent such as LiAlH₄ in a solvent such asbut not limited to diethyl ether or THF. Compounds of Formula (19) canbe prepared from compounds of Formula (18) using Dess-Martin periodinaneor Swern oxidation conditions known to those skilled in the art andreadily available in the literature. Compounds of Formula (19) can bereacted with a compound of Formula (5) and a reducing agent to providecompounds of Formula (20). Examples of reducing agents include sodiumborohydride, sodium cyanoborohydride, sodium triacetoxyborohydride,polymer supported cyanoborohydride, and the like. The reaction istypically performed in a solvent such as but not limited to methanol,tetrahydrofuran, 1,2-dichloroethane, and dichloromethane or mixturesthereof. Compounds of Formula (21) can be prepared from compounds ofFormula (20) as described in SCHEME 1, and can be used as described inSCHEME 7 to prepare compounds of Formula (I).

As shown in SCHEME 5, compounds of Formula (22), wherein R is alkyl, maybe converted to compounds of Formula (23) by reacting the former,wherein X¹ is Cl, Br, I, or CF₃SO₃—, and compounds of Formula R^(50A)—OHand a catalyst, with or without a first base. Examples of catalystsinclude copper(I) trifluoromethanesulfonate toluene complex, PdCl₂,Pd(OAc)₂, and Pd₂(dba)₃. Examples of first bases include triethylamine,N,N-diisopropylethylamine, Cs₂CO₃, Na₂CO₃, K₃PO₄, and mixtures thereof.

Compounds of Formula (22) may also be converted to compounds of Formula(23) by reacting the former, when X¹ is Cl, F, or NO₂, and compounds ofFormula R^(50A)—OH with a first base. Examples of first bases includetriethylamine, N,N-diisopropylethylamine, Cs₂CO₃, Na₂CO₃, K₃PO₄, andmixtures thereof.

Compounds of Formula (18) can be reacted with mesyl chloride and a basesuch as but not limited to triethylamine, followed byN-t-butoxycarbonylpiperazine, to provide compounds of Formula (24).Compounds of Formula (25) can be prepared by reacting compounds ofFormula (24) with triethylsilane and trifluoroacetic acid. Compounds ofFormula (25) can be reacted with compounds of Formula (26) and HK₂PO₄ toprovide compounds of Formula (27) in a solvent such as but not limitedto dimethylsulfoxide. Compounds of Formula (28) can be prepared fromcompounds of Formula (27) as described in SCHEME 1, and can be used asdescribed in SCHEME 7 to prepare compounds of Formula (I).

As shown in SCHEME 7, compounds of Formula (32), which can be preparedas described herein, may be converted to compounds of Formula (33) byreacting the former with ammonia. Compounds of Formula (33) may beconverted to compounds of Formula (I) by reacting the former andcompounds of Formula (4), (8), (14), (21), (23), (28), or (38) and acoupling agent, with or without a first base. Examples of couplingagents include 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimidehydrochloride, 1,1′-carbonyldiimidazole, andbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate.Examples of first bases include triethylamine,N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, and mixturesthereof.

Compounds of Formula (33), prepared as described in SCHEME 7, can alsobe converted to compounds of Formula (I) by reacting the former andcompounds of Formula (34) and a first base. Examples of first basesinclude but are not limited to sodium hydride, triethylamine,N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, and mixturesthereof.

As shown in SCHEME 9, compounds of Formula (35), wherein L is a bond,alkyl, O, S, S(O), S(O)₂, NH, etc., can be reacted with compounds ofFormula (36), to provide compounds of Formula (37). The reaction istypically performed at elevated temperatures in a solvent such as butnot limited to dimethylsulfoxide, and may require the use of a base suchas but not limited to potassium phosphate, potassium carbonate, and thelike. Compounds of Formula (38) can be prepared from compounds ofFormula (37) as described in SCHEME 1, and can be used as described inSCHEME 7 to prepare compounds of Formula (I).

Compounds of Formula (39), wherein Y is as described herein forsubstituents on R³⁷, can be prepared from compounds of Formula (39A)wherein X is a halide or triflate, and Y—B(OH)₂ using Suzuki couplingconditions known to those skilled in the art and readily available inthe literature. Compounds of Formula (39) can be reacted with tert-butylpiperazine-1-carboxylate and a reducing agent such as sodiumtriacetoxyborohydride to provide compounds of Formula (40). The reactionis typically performed in a solvent such as but not limited to methylenechloride. Compounds of Formula (41) can be prepared from compounds ofFormula (40) by reacting the latter with R⁵⁰X, wherein X is a halide,and NaH in a solvent such as N,N-dimethylformamide, and then theresulting material can be treated with triethylsilane andtrifluoroacetic acid in dichloromethane. Compounds of Formula (41) canbe used as described in Scheme 9 wherein CH₂R³⁷ is as shown in Formula(41).

As shown in SCHEME 11, substituted piperazin-2-ones wherein R⁵⁰ isalkyl, can be reacted with compounds of Formula (6a) and a reducingagent such as sodium triacetoxyborohydride in dichloromethane to providecompounds of Formula (42). Compounds of Formula (42) can be reduced tocompounds of Formula (43) using a reducing agent such as but not limitedto lithium aluminum hydride in a solvent such as but not limited totetrahydrofuran. Compounds of Formula (43) can be used as described inScheme 9 wherein CH₂R³⁷ is as shown in Formula (43).

The following examples are presented to provide what is believed to bethe most useful and readily understood description of procedures andconceptual aspects of this invention. The exemplified compounds werenamed using ACD/ChemSketch Version 5.06 (5 Jun. 2001, Advanced ChemistryDevelopment Inc., Toronto, Ontario), or ChemDraw® Ver. 9.0.5(CambridgeSoft, Cambridge, Mass.). Intermediates were named usingChemDraw® Ver. 9.0.5 (CambridgeSoft, Cambridge, Mass.).

Example 14-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamideExample 1A tert-butyl4-((4′-chlorobiphenyl-2-yl)methyl)piperazine-1-carboxylate

4′-Chlorobiphenyl-2-carbaldehyde (EXAMPLE 27C) (4.1 g), tert-butylpiperazine-1-carboxylate (4.23 g), and sodium triacetoxyborohydride(5.61 g) in CH₂Cl₂ (60 mL) were combined stirred for 24 hours. Thereaction was quenched with methanol and poured into ether. The solutionwas washed with water and brine, concentrated, and chromatographed onsilica gel with 2-25% ethyl acetate/hexanes.

Example 1B 1-((4′-chlorobiphenyl-2-yl)methyl)piperazine

EXAMPLE 1A (3.0 g) and triethylsilane (1 mL) were stirred in CH₂Cl₂ (30mL) and trifluoroacetic acid (30 mL) for 2 hours, and the reaction wasconcentrated, and then taken up in ether and concentrated again. Theproduct was used without further purification.

Example 1C methyl 4-fluoro-2-phenoxybenzoate

Methyl 2-bromo-4-fluorobenzoate (1 g), phenol (0.565 g), cesiumcarbonate (1.96 g), copper(I) triflate toluene complex (0.087 g), andethyl acetate (0.034 mL) in toluene (12 mL) was stirred at 110° C. for24 hours. The reaction was cooled and chromatographed on silica gel with5% ethyl acetate/hexanes.

Example 1D methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoate

EXAMPLE 1C (630 mg), EXAMPLE 1B, and K₂CO₃ (707 mg) were stirred indimethylsulfoxide at 125° C. for 5 hours. The reaction was cooled andchromatographed on silica gel with 10% ethyl acetate/hexanes.

Example 1E4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoicacid

EXAMPLE 1D (600 mg) was stirred in 25 mL 2:1 dioxane/1M NaOH at 60° C.for 24 hours. The solution was cooled and adjusted to pH 4 with NaH₂PO₄solution and concentrated HCl, and extracted with ethyl acetate. Theextract was washed with brine and dried (Na₂SO₄), filtered andconcentrated.

Example 1F3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide

4-Fluoro-3-nitrobenzenesulfonamide (2.18 g),(tetrahydropyran-4-yl)methylamine (1.14 g), and triethylamine (1 g) werestirred in tetrahydrofuran (30 mL) for 24 hours. The solution wasdiluted with ethyl acetate, washed with NaH₂PO₄ solution and brine, anddried (Na₂SO₄), filtered and concentrated. The product was trituratedfrom ethyl acetate.

Example 1G4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide

EXAMPLE 1E (90 mg), EXAMPLE 1F (45 mg),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (65 mg),and 4-dimethylaminopyridine (22 mg) were stirred in CH₂Cl₂ (4 mL) for 24hours. The reaction was cooled and chromatographed on silica gel with20-100% ethyl acetate/hexanes. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ11.55 (brs, 1H), 8.63 (t, 1H), 8.47 (d, 1H), 7.75 (d, 1H), 7.46 (m, 6H),7.35 (m, 2H), 7.24 (m, 3H), 7.15 (d, 1H), 6.99 (dd, 1H), 6.82 (d, 2H),6.75 (d, 1H), 6.38 (d, 1H), 3.86 (br d, 2H), 3.49 (m, 2H), 3.37 (br s,2H), 3.15 (br s, 4H), 2.34 (br s, 4H), 1.91 (br s, 4H), 1.64 (br d, 2H),1.29 (m, 3H).

Example 24-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 2A 4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide

4-Aminobenzenesulfonamide (6.80 g), tetrahydropyran-4-carboxaldehyde(4.96 g), and sodium triacetoxyborohydride (16.74 g) in tetrahydrofuran(300 mL) and acetic acid (15 mL) were stirred in for 24 hours. Thereaction was concentrated and taken up in ethyl acetate. The resultingsolution was washed with water and brine, concentrated, andchromatographed on silica gel with 50% ethyl acetate/hexanes.

Example 2B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 2A for EXAMPLE 1F inEXAMPLE 1G. ¹H NMR (500 MHz, dimethylsulfoxide-d₆/D₂O) δ 7.54 (d, 1H),7.46 (m, 8H), 7.36 (m, 4H), 7.24 (d, 1H), 7.13 (dd, 1H), 6.93 (d, 2H),6.75 (d, 1H), 6.55 (d, 2H), 6.30 (d, 1H), 3.86 (dd, 2H), 3.36 (s, 2H),3.28 (t, 2H), 3.10 (br s, 4H), 2.96 (d, 2H), 2.32 (br s, 4H), 1.76 (m,1H), 1.64 (d, 2H), 1.20 (m, 2H).

Example 32-(benzyloxy)-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 3A methyl 2-(benzyloxy)-4-fluorobenzoate

Methyl 4-fluoro-2-hydroxybenzoate (2.00 g), benzyl bromide (1.54 mL),and cesium carbonate (4.60 g) in N,N-dimethylformamide (50 mL) werestirred for 24 hours. The reaction was taken up in ether and washed with3×1M NaOH solution, and brine, then concentrated to give the pureproduct.

Example 3B methyl2-(benzyloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 3A for EXAMPLE 1C inEXAMPLE 1D.

Example 3C2-(benzyloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 3B for EXAMPLE 1D inEXAMPLE 1E.

Example 3D2-(benzyloxy)-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 3C for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 10.90 (br s, 1H),8.66 (m, 1H), 8.59 (s, 1H), 7.82 (d, 1H), 7.33-7.55 (m, 12H), 7.18-7.27(m, 3H), 6.61 (s, 1H), 6.56 (d, 1H), 5.22 (s, 2H), 3.86 (br d, 2H), 3.40(m, 2H), 3.31 (m, 8H), 2.34 (br s, 4H), 1.91 (br s, 2H), 1.64 (br d,2H), 1.29 (m, 3H).

Example 44-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(2-phenylethoxy)benzamideExample 4A methyl 4-fluoro-2-phenethoxybenzoate

Methyl 4-fluoro-2-hydroxybenzoate (1.00 g) and phenethyl alcohol (0.64mL) were added to triphenylphosphine (1.54 g) anddiisopropylazodicarboxylate (1.04 mL) in tetrahydrofuran (20 mL) at 0°C., and the reaction was stirred at room temperature for 24 hours. Themixture was chromatographed on silica gel with 5% ethyl acetate/hexanes.

Example 4B methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenethoxybenzoate

This example was prepared by substituting EXAMPLE 4A for EXAMPLE 1C inEXAMPLE 1D.

Example 4C4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenethoxybenzoicacid

This example was prepared by substituting EXAMPLE 4B for EXAMPLE 1D inEXAMPLE 1E.

Example 4D4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(2-phenylethoxy)benzamide

This example was prepared by substituting EXAMPLE 4C for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 10.75 (br s, 1H),8.66 (m, 2H), 7.91 (d, 1H), 7.47 (m, 6H), 7.20-7.40 (m, 8H), 6.53 (d,1H), 6.47 (s, 1H), 4.35 (t, 2H), 4.03 (m, 1H), 3.85 (br d, 2H), 3.38 (s,2H), 3.25 (m, 8H), 3.13 (t, 2H), 2.36 (br s, 4H), 2.21 (br s, 2H), 1.62(br d, 2H), 1.20 (m, 2H), 1.17 (m, 1H).

Example 54-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(phenylthio)benzamideExample 5A methyl 4-fluoro-2-(phenylthio)benzoate

5-Fluoro-2-(methoxycarbonyl)phenylboronic acid (1.00 g),2-(phenylthio)isoindoline-1,3-dione (0.86 g), and(2-hydroxy-3,5-diisopropylbenzoyloxy)copper (0.29 g) were stirred indioxane (15 mL) at 50° C. for 24 hours. The reaction mixture waschromatographed on silica gel with 5% ethyl acetate/hexanes.

Example 5B methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenylthio)benzoate

This example was prepared by substituting EXAMPLE 5A for EXAMPLE 1C inEXAMPLE 1D.

Example 5C4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenylthio)benzoicacid

This example was prepared by substituting EXAMPLE 5B for EXAMPLE 1D inEXAMPLE 1E.

Example 5D4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(phenylthio)benzamide

This example was prepared by substituting EXAMPLE 5C for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.95 (br s, 1H),8.59 (m, 2H), 7.93 (d, 1H), 7.63 (d, 1H), 7.15-7.50 (m, 14H), 6.73 (d,1H), 6.18 (s, 1H), 3.82 (dd, 2H), 3.36 (m, 4H), 3.32 (m, 2H), 2.94 (brs, 4H), 2.30 (br s, 4H), 1.64 (m, 1H), 1.61 (m, 2H), 1.25 (m, 2H).

Example 64-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(phenylthio)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 5C for EXAMPLE 1E andEXAMPLE 2A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz,dimethylsulfoxide-d₆/D₂O) δ 7.65 (d, 2H), 7.55 (d, 1H), 7.33-7.48 (m,12H), 7.24 (m, 2H), 6.73 (d, 1H), 6.66 (d, 2H), 6.17 (d, 1H), 3.85 (dd,2H), 3.34 (s, 2H), 3.26 (t, 2H), 2.98 (d, 2H), 2.92 (br s, 4H), 2.25 (brs, 4H), 1.78 (m, 1H), 1.63 (d, 2H), 1.20 (m, 2H).

Example 74-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(phenylthio)benzamideExample 7A 4-(3-morpholinopropylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting3-(N-morpholinyl)-1-propylamine for (tetrahydropyran-4-yl)methylamine inEXAMPLE 1F.

Example 7B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(phenylthio)benzamide

This example was prepared by substituting EXAMPLE 5C for EXAMPLE 1E andEXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 10.20 (br s, 1H), 8.69 (m, 1H), 8.57 (d, 1H),7.95 (dd, 2H), 7.71 (m, 1H), 7.31-7.51 (m, 10H), 7.12-7.26 (m, 3H), 6.68(dd, 1H), 6.07 (m, 1H), 4.06 (s, 2H), 3.68 (m, 4H), 3.50 (m, 2H), 3.32(m, 6H), 2.88 (m, 4H), 2.27 (m, 4H), 1.91 (m, 2H).

Example 84-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(phenylsulfonyl)benzamideExample 8A methyl 4-fluoro-2-(phenylsulfonyl)benzoate

EXAMPLE 5A (0.30 g) and KMnO₄ (1.80 g) were stirred in acetic acid (40mL) at 60° C. for 24 hours. The reaction mixture was filtered through aplug of silica gel, concentrated, and chromatographed on silica gel with50% ethyl acetate/hexanes.

Example 8B methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenylsulfonyl)benzoate

This example was prepared by substituting EXAMPLE 8A for EXAMPLE 1C inEXAMPLE 1D.

Example 8C4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenylsulfonyl)benzoicacid

This example was prepared by substituting EXAMPLE 8B for EXAMPLE 1D inEXAMPLE 1E.

Example 8D4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(phenylsulfonyl)benzamide

This example was prepared by substituting EXAMPLE 8C for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.95 (br s, 1H),8.54 (s, 1H), 8.41 (dd, 1H), 7.90 (m, 2H), 7.82 (d, 1H), 7.76 (d, 1H),7.66 (m, 1H), 7.46 (m, 5H), 7.40 (m, 4H), 7.11 (m, 2H), 6.67 (dd, 1H),6.62 (m, 1H), 4.36 (m, 1H), 3.82 (dd, 2H), 3.39 (m, 6H), 3.19 (m, 6H),2.37 (br s, 4H), 1.91 (m, 1H), 1.63 (m, 2H), 1.26 (m, 2H).

Example 94-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(phenylsulfinyl)benzamideExample 9A methyl 4-fluoro-2-(phenylsulfinyl)benzoate

OXONE® (Dupont) (5.60 g) was added portionwise over 1 hour to EXAMPLE 5A(1.00 g) in a mixture of acetic acid (30 mL), water (30 mL) and CH₂Cl₂(20 mL), and the reaction was stirred for an additional 1 hour. Thereaction mixture was taken up in ethyl acetate, washed with Na₂S₂O₃solution, water, and brine, concentrated, and chromatographed on silicagel with 5-25% ethyl acetate/hexanes.

Example 9B methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenylsulfinyl)benzoate

This example was prepared by substituting EXAMPLE 9A for EXAMPLE 1C inEXAMPLE 1D.

Example 9C4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenylsulfinyl)benzoicacid

This example was prepared by substituting EXAMPLE 9B for EXAMPLE 1D inEXAMPLE 1E.

Example 9D4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(phenylsulfinyl)benzamide

This example was prepared by substituting EXAMPLE 9C for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (500 MHz, dimethylsulfoxide-d₆/D₂O) δ 8.51 (s, 1H),7.85 (dd, 2H), 7.64 (d, 2H), 7.48 (m, 8H), 7.32 (m, 1H), 7.23 (m, 1H),7.14 (m, 4H), 6.97 (d, 1H), 3.85 (dd, 2H), 3.35 (d, 2H), 3.34 (m, 6H),3.27 (t, 2H), 2.74 (br s, 4H), 1.93 (m, 1H), 1.64 (d, 2H), 1.28 (m, 2H).

Example 102-benzyl-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 10A methyl 2-benzyl-4-fluorobenzoate

5-Fluoro-2-(methoxycarbonyl)phenylboronic acid (1.00 g), benzyl bromide(0.50 mL), K₂CO₃ (1.75 g), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(PdCl₂(dppf)) (0.17 g) were stirred in tetrahydrofuran (20 mL) at 60° C.for 24 hours. The reaction mixture was chromatographed on silica gelwith 2% ethyl acetate/hexanes.

Example 10B methyl2-benzyl-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 10A for EXAMPLE 1C inEXAMPLE 1D.

Example 10C2-benzyl-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 10B for EXAMPLE 1D inEXAMPLE 1E.

Example 10D2-benzyl-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 100C for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (500 MHz, dimethylsulfoxide-d₆/D₂O) δ 8.55 (d, 1H),7.90 (d, 1H), 7.38-7.56 (m, 10H), 7.25 (m, 2H), 6.96 (d, 2H), 6.83 (s,2H), 6.75 (d, 1H), 4.06 (s, 2H), 3.85 (dd, 2H), 3.48 (s, 2H), 3.37 (d,2H), 3.25 (t, 2H), 3.20 (br s, 4H), 2.44 (br s, 4H), 1.91 (m, 1H), 1.63(d, 2H), 1.29 (m, 2H).

Example 112-benzyl-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 100C for EXAMPLE 1Eand EXAMPLE 2A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.70 (br s, 1H), 7.48 (m, 6H), 6.88 (m, 6H),6.62 (m, 6H), 6.42 (dd, 2H), 3.83 (dd, 4H), 3.24 (m, 6H), 2.96 (m, 4H),1.82 (m, 2H), 1.63 (m, 3H), 1.18 (m, 4H).

Example 122-benzyl-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 100C for EXAMPLE 1Eand EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.90 (br s, 1H), 8.80 (m, 1H), 8.54 (d, 1H),7.91 (dd, 1H), 7.48 (m, 7H), 7.40 (d, 2H), 7.26 (d, 2H), 6.97 (dd, 2H),6.86 (m, 2H), 6.76 (d, 1H), 4.04 (m, 5H), 3.72 (m, 4H), 3.56 (m, 2H),3.40 (m, 8H), 3.21 (m, 4H), 2.34 (m, 2H), 1.98 (m, 2H).

Example 134-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(2-phenylethyl)benzamideExample 13A methyl 4-fluoro-2-phenethylbenzoate

Methyl 2-bromo-4-fluorobenzoate (1.00 g), (E)-styrylboronic acid (0.89g), tetrakis(triphenylphosphine)palladium(0) (0.50 g), and K₃PO₄ (2.28g) were stirred in dioxane (17 mL) at 90° C. for 24 hours. The reactionmixture chromatographed on silica gel with 1-5% ethyl acetate/hexanes.The product in methanol (10 ml) was added to 20 wt % of fresh dry 5%Pd—C and stirred 4 days with H₂ in a pressure bottle. The mixture wasfiltered through a nylon membrane and concentrated.

Example 13B methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenethylbenzoate

This example was prepared by substituting EXAMPLE 13A for EXAMPLE 1C inEXAMPLE 1D.

Example 13C4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenethylbenzoicacid

This example was prepared by substituting EXAMPLE 13B for EXAMPLE 1D inEXAMPLE 1E.

Example 13D4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)-2-phenethylbenzamide

This example was prepared by substituting EXAMPLE 13C for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (500 MHz, dimethylsulfoxide-d₆/D₂O) δ 8.62 (d, 1H),7.95 (d, 1H), 7.91 (m, 1H), 7.35-7.52 (m, 6H), 7.19 (m, 2H), 7.13 (m,2H), 6.99 (m, 4H), 6.83 (d, 1H), 6.70 (d, 1H), 6.65 (s, 1H), 3.80 (m,2H), 3.24 (m, 2H), 3.18 (t, 2H), 3.11 (br s, 4H), 2.91 (t, 2H), 2.48 (m,2H), 2.38 (br s, 4H), 1.81 (m, 1H), 1.54 (d, 2H), 1.23 (m, 2H).

Example 142-(benzylamino)-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 14A methyl 2-(benzylamino)-4-fluorobenzoate

Methyl 2-amino-4-fluorobenzoate (0.90 g), benzaldehyde (0.54 mL), sodiumtriacetoxyborohydride (1.58 g) and acetic acid (0.3 mL) in CH₂Cl₂ (20mL) were stirred for 3 hours. The reaction was quenched with methanol,concentrated, and chromatographed on silica gel with 5% ethylacetate/hexanes.

Example 14B methyl2-(benzylamino)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 14A for EXAMPLE 1C inEXAMPLE 1D.

Example 14C2-(benzylamino)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 14B for EXAMPLE 1D inEXAMPLE 1E.

Example 14D2-(benzylamino)-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 14C for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (500 MHz, dimethylsulfoxide-d₆/D₂O) δ 8.58 (d, 1H),7.92 (d, 1H), 7.87 (m, 1H), 7.59 (d, 2H), 7.48 (m, 2H), 7.43 (m, 4H),7.20-7.29 (m, 8H), 6.15 (d, 1H), 4.32 (s, 2H), 3.85 (m, 2H), 3.49 (m,2H), 3.33 (m, 2H), 3.26 (t, 2H), 3.12 (br s, 4H), 2.39 (br s, 4H), 1.90(m, 1H), 1.62 (d, 2H), 1.27 (m, 2H).

Example 152-anilino-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 15A methyl 4-fluoro-2-(phenylamino)benzoate

Methyl 2-bromo-4-fluorobenzoate (1.00 g), aniline (0.47 mL),palladium(II) acetate (0.048 g),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.214 g) and Cs₂CO₃ (2.08g) in toluene (12 mL) were stirred at 90° C. for 24 hours. The reactionwas concentrated and chromatographed on silica gel with 5-50% ethylacetate/hexanes.

Example 15B methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenylamino)benzoate

This example was prepared by substituting EXAMPLE 15A for EXAMPLE 1C inEXAMPLE 1D.

Example 15C4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenylamino)benzoicacid

This example was prepared by substituting EXAMPLE 15B for EXAMPLE 1D inEXAMPLE 1E.

Example 15D2-anilino-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 15C for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.55 (br s, 1H),8.56 (m, 2H), 7.92 (d, 1H), 7.72 (d, 1H), 7.47 (m, 6H), 7.25 (m, 4H),7.12 (d, 2H), 6.95 (m, 2H), 6.53 (s, 1H), 6.38 (dd, 1H), 3.81 (dd, 2H),3.37 (br s, 4H), 3.12 (br s, 4H), 2.41 (br s, 4H), 1.91 (m, 1H), 1.61(br d, 2H), 1.23 (m, 4H).

Example 162-anilino-4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 15C for EXAMPLE 1E andEXAMPLE 2A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz,dimethylsulfoxide-d₆/D₂O) δ 7.78 (d, 1H), 7.52 (d, 2H), 7.47 (m, 6H),7.36 (m, 3H), 7.27 (m, 3H), 7.11 (m, 2H), 6.90 (m, 1H), 6.61 (s, 1H),6.53 (d, 1H), 6.31 (d, 1H), 4.46 (s, 1H), 3.82 (m, 2H), 3.37 (s, 2H),3.26 (t, 2H), 3.05 (br s, 4H), 2.93 (d, 2H), 2.37 (br s, 4H), 1.77 (m,1H), 1.63 (d, 2H), 1.20 (m, 2H).

Example 174-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-methoxy-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 17A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-methoxybenzoate

Methyl 4-bromo-2-methoxybenzoic acid (700 mg), EXAMPLE 1B (983 mg),K₃PO₄ (909 mg), tris(dibenzylideneacetone)dipalladium(0) (78 mg), and2-(di-t-butylphosphino)biphenyl (102 mg) were stirred in1,2-dimethoxyethane (10 mL) at 80° C. for 24 hours. The reaction mixturewas chromatographed on silica gel with 20-50% ethyl acetate/hexanes.

Example 17B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-methoxybenzoicacid

This example was prepared by substituting EXAMPLE 17A for EXAMPLE 1D inEXAMPLE 1E.

Example 17C4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-methoxy-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 17B for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 10.81 (br s, 1H),8.64 (m, 2H), 7.96 (d, 1H), 7.20-7.54 (m, 10H), 6.52 (d, 1H), 6.46 (s,1H), 3.90 (s, 3H), 3.40 (m, 4H), 3.27 (br s, 4H), 2.39 (br s, 4H), 1.91(m, 1H), 1.62 (br d, 2H), 1.27 (m, 4H).

Example 184-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamideExample 18A methyl4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

To a suspension of hexane washed NaH (17 g) in dichloromethane (700 mL),5,5-dimethyl-2-methoxycarbonylcyclohexanone (38.5 g) was added dropwiseat 0° C. After stirring for 30 minutes, the mixture was cooled to −78°C. and trifluoromethanesulfonic anhydride (40 mL) was added. Thereaction mixture was warmed to room temperature and stirred for 24hours. The organic layer was washed with brine, dried, and concentratedto give the product.

Example 18B methyl2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarboxylate

EXAMPLE 18A (62.15 g), 4-chlorophenylboronic acid (32.24 g), CsF (64 g)and tetrakis(triphenylphosphine)palladium(0) (2 g) in 2:11,2-dimethoxyethane/methanol (600 mL) were heated to 70° C. for 24hours. The mixture was concentrated. Ether (4×200 mL) was added and themixture was filtered. The combined ether solution was concentrated togive the product.

Example 18C (2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methanol

To a mixture of LiBH₄ (13 g), EXAMPLE 18B (53.8 g) and ether (400 mL),methanol (25 mL) was added slowly by syringe. The mixture was stirred atroom temperature for 24 hours. The reaction was quenched with 1N HClwith ice-cooling. The mixture was diluted with water and extracted byether (3×100 mL). The extracts were dried, and concentrated. The crudeproduct was chromatographed on silica gel with 0-30% ethylacetate/hexanes.

Example 18D methyl 2-bromo-4-(piperazin-1-yl)benzoate

This example was prepared by substituting piperazine for EXAMPLE 1B andmethyl 2-bromo-4-fluorobenzoate for EXAMPLE 1C in EXAMPLE 1D.

Example 18E methyl2-bromo-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

MsCl (7.5 mL) was added via syringe to EXAMPLE 18C (29.3 g) andtriethylamine (30 mL) in CH₂Cl₂ (500 mL) at 0° C., and the mixture wasstirred for 1 minute. EXAMPLE 18D (25 g) was added and the reaction wasstirred at room temperature for 24 hours. The suspension was washed withbrine, dried, and concentrated. The crude product was chromatographed onsilica gel with 10-20% ethyl acetate/hexanes.

Example 18F methyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-phenoxybenzoate

EXAMPLE 18E (500 mg), phenol (195 mg), Cs₂CO₃ (674 mg), 1-naphthoic acid(356 mg), copper (I) triflate-toluene complex (45 mg), ethyl acetate(0.016 mL), and 4A sieves (50 mg) in toluene (2 mL) was stirred at 105°C. for 24 hours. The reaction was cooled and taken up in ethyl acetate(100 mL) and water (40 mL). The layers were separated and the organiclayer was washed with 2×Na₂CO₃ solution and brine, dried, andconcentrated. The crude product was chromatographed on silica gel with20% ethyl acetate/hexanes.

Example 18G4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-phenoxybenzoicacid

This example was prepared by substituting EXAMPLE 18F for EXAMPLE 1D inEXAMPLE 1E.

Example 18H4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 18G for EXAMPLE 1E andEXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.10 (br s, 1H), 8.76 (m, 1H), 8.46 (d, 1H),7.76 (dd, 1H), 7.50 (d, 1H), 7.35 (d, 2H), 7.23 (d, 2H), 7.06 (dd, 2H),6.99 (dd, 1H), 6.81 (d, 2H), 6.74 (d, 1H), 6.34 (s, 1H), 3.62 (m, 4H),3.46 (m, 2H), 3.13 (m, 4H), 2.76 (m, 2H), 2.48 (m, 2H), 2.22 (m, 6H),1.97 (m, 2H), 1.82 (m, 2H), 1.40 (t, 2H), 1.06 (m, 7H), 0.94 (s, 3H).

Example 194-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamideExample 19A methyl5,5-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

This example was prepared by substituting4,4-dimethyl-2-methoxycarbonylcyclohexanone for5,5-dimethyl-2-methoxycarbonylcyclohexanone in EXAMPLE 18A.

Example 19B methyl2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enecarboxylate

This example was prepared by substituting EXAMPLE 19A for EXAMPLE 18A inEXAMPLE 18B.

Example 19C (2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methanol

This example was prepared by substituting EXAMPLE 19B for EXAMPLE 18B inEXAMPLE 18C.

Example 19D methyl2-bromo-4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 19C for EXAMPLE 18C inEXAMPLE 18E.

Example 19E methyl4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-phenoxybenzoate

This example was prepared by substituting EXAMPLE 19D for EXAMPLE 18E inEXAMPLE 18F.

Example 19F4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-phenoxybenzoicacid

This example was prepared by substituting EXAMPLE 19E for EXAMPLE 1D inEXAMPLE 1E.

Example 19G4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 19F for EXAMPLE 1E andEXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.10 (br s, 1H), 8.71 (m, 1H), 8.42 (d, 1H),7.73 (dd, 1H), 7.53 (d, 1H), 7.34 (d, 2H), 7.21 (dd, 2H), 7.10 (d, 2H),6.96 (dd, 1H), 6.78 (d, 2H), 6.70 (d, 1H), 6.32 (s, 1H), 3.61 (m, 4H),3.44 (m, 2H), 3.09 (m, 4H), 2.71 (m, 2H), 2.44 (m, 4H), 2.21 (m, 4H),1.96 (m, 2H), 1.79 (m, 2H), 1.47 (t, 2H), 1.17 (m, 3H), 1.08 (m, 4H),0.95 (s, 3H).

Example 204-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 20A ethyl 2-(1H-indazol-5-yloxy)-4-fluorobenzoate

Ethyl 2,4-difluorobenzoate (1.14 g), K₃PO₄ (1.30 g) and5-hydroxyindazole (0.90 g) were stirred at 110° C. in diglyme (12 mL)for 24 hours. The reaction was cooled and poured into ether. Thesolution was washed three times with 1M NaOH solution, and brine, anddried. The solution was then concentrated, and the crude product waschromatographed on silica gel with 20% ethyl acetate/hexanes.

Example 20B tert-butyl4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate

This example was prepared by substituting N-t-butoxycarbonylpiperazinefor EXAMPLE 18D in EXAMPLE 18E.

Example 20C1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazine

This EXAMPLE was prepared by substituting EXAMPLE 20B for EXAMPLE 1A inEXAMPLE 1B.

Example 20D ethyl2-(1H-indazol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

EXAMPLE 20A (330 mg), EXAMPLE 20C (335 mg), and HK₂PO₄ (191 mg) werestirred in dimethylsulfoxide (5 mL) at 140° C. for 24 hours. Thereaction was diluted with ethyl acetate, washed three times with water,washed with brine, dried, and concentrated. The crude product waschromatographed on silica gel with 30% ethyl acetate/hexanes.

Example 20E2-(1H-indazol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 20D for EXAMPLE 1D inEXAMPLE 1E.

Example 20F4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 20E for EXAMPLE 1E andEXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 13.03 (br s, 1H), 11.25 (br s, 1H), 8.70 (m,1H), 8.48 (d, 1H), 7.94 (dd, 1H), 7.68 (dd, 1H), 7.52 (m, 2H), 7.34 (d,2H), 7.06 (m, 4H), 6.96 (dd, 1H), 6.88 (d, 1H), 6.23 (s, 1H), 3.61 (m,4H), 3.44 (m, 2H), 3.05 (m, 4H), 2.73 (m, 2H), 2.42 (m, 4H), 2.18 (m,4H), 1.99 (m, 2H), 1.91 (d, 2H), 1.78 (m, 2H), 1.39 (t, 2H), 1.17 (m,2H), 0.93 (s, 6H).

Example 214-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 21A 4-(1-methylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting 4-amino-N-methylpiperidine for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 21B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 20E for EXAMPLE 1E andEXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 12.80 (br s, 1H), 10.70 (br s, 1H), 8.34 (s,1H), 8.02 (d, 1H), 7.87 (d, 1H), 7.70 (dd, 1H), 7.55 (m, 2H), 7.36 (d,2H), 7.06 (m, 2H), 6.95 (m, 1H), 6.72 (d, 1H), 6.62 (d, 1H), 6.24 (s,1H), 3.35 (m, 4H), 3.18 (m, 2H), 3.00 (m, 2H), 2.80 (m, 4H), 2.73 (m,2H), 2.20 (m, 4H), 1.99 (m, 2H), 1.91 (s, 3H), 1.54 (m, 1H), 1.41 (t,2H), 1.22 (m, 2H), 1.09 (s, 6H).

Example 224-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1,2,3,4-tetrahydroquinolin-6-yloxy)benzamideExample 22A ethyl4-fluoro-2-(1,2,3,4-tetrahydroquinolin-6-yloxy)benzoate

This example was prepared by substituting5-hydroxy-1,2,3,4-tetrahydroquinoline for 5-hydroxyindazole in EXAMPLE20A.

Example 22B ethyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(1,2,3,4-tetrahydroquinolin-6-yloxy)benzoate

This example was prepared by substituting EXAMPLE 22A for EXAMPLE 20A inEXAMPLE 20D.

Example 22C4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(1,2,3,4-tetrahydroquinolin-6-yloxy)benzoicacid

This example was prepared by substituting EXAMPLE 22B for EXAMPLE 1D inEXAMPLE 1E.

Example 22D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(1,2,3,4-tetrahydroquinolin-6-yloxy)benzamide

This example was prepared by substituting EXAMPLE 22C for EXAMPLE 1E andEXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 10.95 (br s, 1H), 8.83 (m, 1H), 8.60 (d, 1H),7.90 (dd, 1H), 7.46 (d, 1H), 7.35 (d, 2H), 7.21 (dd, 2H), 7.06 (d, 2H),6.62 (m, 2H), 6.42 (d, 1H), 6.11 (d, 1H), 5.61 (br s, 1H), 4.02 (m, 1H),3.61 (m, 4H), 3.48 (m, 2H), 3.17 (m, 2H), 3.07 (m, 4H), 2.74 (m, 2H),2.63 (m, 2H), 2.44 (m, 4H), 2.19 (m, 4H), 1.97 (m, 4H), 1.79 (m, 4H),1.41 (t, 2H), 1.17 (m, 4H), 0.94 (s, 6H).

Example 234-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1,2,3,4-tetrahydroquinolin-6-yloxy)benzamide

This example was prepared by substituting EXAMPLE 22C for EXAMPLE 1E andEXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.10 (br s, 1H), 8.71 (m, 1H), 8.42 (d, 1H),7.73 (dd, 1H), 7.53 (d, 1H), 7.34 (d, 2H), 7.21 (dd, 2H), 7.10 (d, 2H),6.96 (dd, 1H), 6.78 (d, 2H), 6.70 (d, 1H), 6.32 (s, 1H), 3.61 (m, 4H),3.44 (m, 2H), 3.09 (m, 4H), 2.71 (m, 2H), 2.44 (m, 4H), 2.21 (m, 4H),1.96 (m, 2H), 1.79 (m, 2H), 1.47 (t, 2H), 1.17 (m, 3H), 1.08 (m, 4H),0.95 (s, 3H).

Example 244-(4-{[4′-chloro-4-(pyrrolidin-1-ylmethyl)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 24A methyl 5-formyl-2-(trifluoromethylsulfonyloxy)benzoate

Triflic anhydride (7.74 mL) was added to methyl5-formyl-2-hydroxybenzoate (7.5 g) in 150 mL CH₂Cl₂ at 0° C., and thereaction was stirred and allowed to warm to room temperature over 3hours. The reaction was diluted with CH₂Cl₂ (150 mL), washed with 3×brine, dried over Na₂SO₄, and concentrated. The product was used withoutfurther purification.

Example 24B methyl 4′-chloro-4-formylbiphenyl-2-carboxylate

EXAMPLE 24A (14.5 g), 4-chlorophenylboronic acid (6.88 g) CsF (12.2 g),and tetrakis(triphenylphosphine)palladium(0) were stirred at 70° C. for24 hours. The reaction was cooled, filtered, and concentrated. The crudeproduct was taken up in ethyl acetate (250 mL), washed with 3×1M NaOH,and brine, concentrated, and chromatographed on silica gel with 10%ethyl acetate/hexanes.

Example 24C methyl4′-chloro-4-(pyrrolidin-1-ylmethyl)biphenyl-2-carboxylate

This example was prepared by substituting EXAMPLE 24B for4′-chlorobiphenyl-2-carboxaldehyde and pyrrolidine for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 24D (4′-chloro-4-(pyrrolidin-1-ylmethyl)biphenyl-2-yl)methanol

DIBAL in hexanes (1M, 5.9 mL) was added to EXAMPLE 24C (650 mg) inCH₂Cl₂ (30 mL) at 0° C., and the reaction was stirred for 20 minutes.The reaction was quenched by the slow addition of methanol (2 mL), and1M NaOH (10 mL), and the resulting solution was extracted twice withethyl acetate. The extracts were washed with brine, dried over Na₂SO₄,and concentrated. The product was used without further purification.

Example 24E 4′-chloro-4-(pyrrolidin-1-ylmethyl)biphenyl-2-carbaldehyde

Dess-Martin periodinane (1.30 g) was added to EXAMPLE 24D (770 mg) inCH₂Cl₂ (30 mL) at room temperature and the reaction was stirred for 24hours. The reaction mixture was concentrated and chromatographed onsilica gel with 1% triethylamine in 25% ethyl acetate/hexanes.

Example 24F methyl 2-(1H-indol-4-yloxy)-4-fluorobenzoate

This example was prepared by substituting 4-hydroxyindole for5-hydroxyindazole and methyl 2,4-difluorobenzoate for ethyl2,4-difluorobenzoate in EXAMPLE 20A.

Example 24G tert-butyl4-(3-(1H-indol-4-yloxy)-4-(methoxycarbonyl)phenyl)piperazine-1-carboxylate

This example was prepared by substituting EXAMPLE 24F for EXAMPLE 20Aand tert-butyl piperazine-1-carboxylate for EXAMPLE 20C in EXAMPLE 20D.

Example 24H methyl 2-(1H-indol-4-yloxy)-4-(piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 24G for EXAMPLE 1A inEXAMPLE 1B.

Example 24I methyl2-(1H-indol-4-yloxy)-4-(4-((4′-chloro-4-(pyrrolidin-1-ylmethyl)biphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 24E for4′-chlorobiphenyl-2 carboxaldehyde and EXAMPLE 24H for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 24J2-(1H-indol-4-yloxy)-4-(4-((4′-chloro-4-(pyrrolidin-1-ylmethyl)biphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 241 for EXAMPLE 1D inEXAMPLE 1E.

Example 24K4-(4-{[4′-chloro-4-(pyrrolidin-1-ylmethyl)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 24J for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.52 (br s, 1H),11.26 (s, 1H), 10.68 (br s, 1H), 8.61 (dd, 1H), 8.49 (s, 1H), 8.19 (brs, 1H), 7.66 (d, 2H), 7.54 (m, 3H), 7.36 (m, 2H), 7.28 (s, 1H), 7.24 (d,1H), 7.05 (d, 1H), 6.95 (dd, 1H), 6.75 (d, 1H), 6.35 (m, 2H), 6.26 (s,1H), 4.38 (m, 3H), 3.85 (dd, 2H), 3.61 (m, 4H), 3.24 (m, 4H), 3.09 (m,4H), 2.85 (m, 2H), 2.35 (m, 2H), 2.02 (m, 2H), 1.87 (m, 4H), 1.60 (m,2H), 1.25 (m, 2H).

Example 254-(4-{[4′-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 25A methyl 4′-chloro-4-(2-oxoethyl)biphenyl-2-carboxylate

To a solution of (methoxymethyl)diphenylphosphine oxide (1.62 g) in 40mL tetrahydrofuran at −78° C., was added lithium diisopropylamide (2M,3.3 mL), and after stirring 3 minutes, EXAMPLE 24B (1.57 g) was added,and the solution was warmed to room temperature. NaH (230 mg), and 40 mLN,N-dimethylformamide were added, and the mixture was heated to 60° C.for 1 hours. The reaction was cooled and poured into NaH₂PO₄ solution.The resulting solution was extracted twice with ether, and the combinedextracts were washed twice with water, and brine, and concentrated. Thecrude mixture of enol ethers was taken up in 1M HCl (50 mL) and dioxane(50 mL), and stirred at 60° C. for 3 hours. The reaction was cooled andpoured into NaHCO₃ solution. The resulting solution was extracted twicewith ether, and the combined extracts were washed with water, and brine,and concentrated. The product was used without further purification.

Example 25B methyl4′-chloro-4-(2-(pyrrolidin-1-yl)ethyl)biphenyl-2-carboxylate

This example was prepared by substituting EXAMPLE 25A for4′-chlorobiphenyl-2-carboxaldehyde and pyrrolidine for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 25C(4′-chloro-4-(2-(pyrrolidin-1-yl)ethyl)biphenyl-2-yl)methanol

This example was prepared by substituting EXAMPLE 25B for EXAMPLE 24C inEXAMPLE 24D.

Example 25D4′-chloro-4-(2-(pyrrolidin-1-yl)ethyl)biphenyl-2-carbaldehyde

This example was prepared by substituting EXAMPLE 25C for EXAMPLE 24D inEXAMPLE 24E.

Example 25E methyl2-(1H-indol-4-yloxy)-4-(4-((4′-chloro-4-(2-(pyrrolidin-1-yl)ethyl)biphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 25D for4′-chlorobiphenyl-2 carboxaldehyde and EXAMPLE 24H for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 25F2-(1H-indol-4-yloxy)-4-(4-((4′-chloro-4-(2-(pyrrolidin-1-yl)ethyl)biphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 25E for EXAMPLE 1D inEXAMPLE 1E.

Example 25G4-(4-{[4′-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 25F for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.15 (s, 1H), 8.47(t, 1H), 8.42 (s, 1H), 7.68 (dd, 1H), 7.58 (d, 1H), 7.44 (m, 4H), 7.22(m, 3H), 7.10 (d, 1H), 6.92 (m, 2H), 6.68 (d, 1H), 6.34 (d, 1H), 6.26(s, 2H), 3.87 (dd, 2H), 3.61 (m, 4H), 3.10-3.24 (m, 11H), 2.97 (m, 4H),2.31 (m, 4H), 1.89 (m, 4H), 1.61 (m, 2H), 1.26 (m, 2H).

Example 264-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamideExample 26A ethyl 2-(1H-indol-5-yloxy)-4-fluorobenzoate

This example was prepared by substituting 5-hydroxyindole for5-hydroxyindazole in EXAMPLE 20A.

Example 26B ethyl2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 26A for EXAMPLE 20A inEXAMPLE 20D.

Example 26C2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 26B for EXAMPLE 1D inEXAMPLE 1E.

Example 26D4-(1-cyclopentylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting 1-cyclopentylpiperidin-4-aminefor (tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 26E4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopentylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 26D for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.13 (br s, 1H), 8.52 (s, 1H), 8.14 (d, 1H),7.80 (d, 1H), 7.52 (d, 1H), 7.35 (m, 4H), 7.04 (m, 4H), 6.80 (d, 1H),6.61 (d, 1H), 6.36 (s, 1H), 6.14 (s, 1H), 5.76 (s, 1H), 3.84 (m, 2H),3.24 (m, 4H), 2.99 (m, 4H), 2.85 (m, 2H), 2.71 (m, 2H), 2.16 (m, 6H),1.95 (m, 4H), 1.50-1.70 (m, 6H), 1.38 (m, 2H), 1.17 (m, 2H), 0.93 (s,6H).

Example 274-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]-3-isobutylpiperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamideExample 27A methyl 2-bromo-4-methylpentanoate

To concentrated HBr (48%) (20 mL) in water (214 mL), was added KBr (17.6g, cooled to 0° C., then sodium nitrite (5.2 g) all at once, thenDL-leucine (5.2 g) in a few portions. The reaction was mechanicallystirred at 0° C. for 1.5 hours, then extracted with 2×200 mL ethylacetate. The combined organic layers were washed with brine and driedover Na₂SO₄. After filtration and concentration, the resultant oil wasdissolved in CH₂Cl₂/methanol and treated with 2.0M (TMS)CHN₂ in ether(30 mL) at room temperature for 10 minutes. The reaction wasconcentrated and then purified by flash chromatography using 97.5/2.5hexane/ethyl acetate.

Example 27B 3-isobutylpiperazin-2-one

EXAMPLE 27A (2.2 g) in ethanol (15 mL) was added dropwise over a periodof 2.5 hours to a stirred refluxing solution of ethane-1,2-diamine (13.2mL) in ethanol (60 mL). Heating was continued for another 2.5 hours,then NaOEt in ethanol was added (21% by wt, 4.0 mL) and heated foranother 90 minutes. The reaction was then cooled and concentrated. Aftertrituration with ether, the title compound was used withoutpurification.

Example 27C 4′-chlorobiphenyl-2-carbaldehyde

To 2-bromobenzaldehyde (2.3 ml) andtetrakis(triphenylphosphine)palladium(0) (0.35 g) in toluene (50 mL),was added 4-chlorophenylboronic acid (4.0 g) and 2M Na₂CO₃ (70 ml). Themixture was heated under reflux for one hour. The reaction was cooled,diluted with water and extracted with ethyl acetate. The organic layerwas washed with brine and the combined aqueous layers back-extractedwith ethyl acetate. The combined organic layers were dried over Na₂SO₄.The crude material was purified by flash chromatography using 97.5/2.5hexane/ethyl acetate.

Example 27D 4-((4′-chlorobiphenyl-2-yl)methyl)-3-isobutylpiperazin-2-one

This example was prepared by substituting EXAMPLE 27B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 27E 1-((4′-chlorobiphenyl-2-yl)methyl)-2-isobutylpiperazine

To a solution of EXAMPLE 27D in tetrahydrofuran (3.6 mL) was addedborane-methyl sulfide complex (10M in tetrahydrofuran) (0.24 mL). Thereaction was heated under reflux for 16 hours, then cooled in anice/water bath. Methanol (5 mL) was added carefully, and the mixture wasstirred cold for 75 minutes. Then 4N HCl in dioxane (0.65 mL) was addedand the reaction heated under reflux for 60 minutes. After cooling toroom temperature, 1N NH₄OH (2.6 mL) was added and the reaction wasstirred for 15 minutes. Then the reaction was concentrated, redissolvedin methanol, concentrated, redissolved in toluene and concentrated. Thecrude solids were slurried in CHCl₃/methanol, the solids were filteredoff, and the filtrate concentrated to afford the title compound.

Example 27F methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)-3-isobutylpiperazin-1-yl)-2-phenoxybenzoate

This example was prepared by substituting EXAMPLE 27E for EXAMPLE 1B inEXAMPLE 1D.

Example 27G4-(4-((4′-chlorobiphenyl-2-yl)methyl)-3-isobutylpiperazin-1-yl)-2-phenoxybenzoicacid

This example was prepared by substituting EXAMPLE 27F for EXAMPLE 1D inEXAMPLE 1E.

Example 27H4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]-3-isobutylpiperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide

EXAMPLE 27G (13 mg), EXAMPLE 1F (7 mg),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (8 mg),and 4-dimethylaminopyridine (5 mg) were stirred in CH₂Cl₂ (1 mL) for 24hours. The product was purified by preparative HPLC using a C18 column,250×50 mm, 10, and eluting with a gradient of 20-100% CH₃CN vs. 0.1%trifluoroacetic acid in water, giving the product as a trifluoroacetatesalt. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.62 (br s, 1H), 9.10(br s, 1H), 8.65 (t, 1H), 8.47 (d, 1H), 7.77 (dd, 1H), 7.70 (br s, 1H),7.50 (m, 5H), 7.39 (m, 3H), 7.25 (m, 2H), 7.18 (d, 1H), 7.01 (dd, 1H),6.83 (m, 2H), 6.76 (m, 1H), 6.40 (br s, 1H), 4.70 and 4.15 (both v br s,total 1H), 3.85 (dd, 2H), 3.60 (v br s, 1H), 3.32, 3.27, 3.24, 3.06 (allm, total 11H), 1.90 (m, 1H), 1.62 (m, 3H), 1.30 (m, 4H), 0.70 (br m,6H).

Example 284-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-(2,4-dioxo-3-azabicyclo[3.2.0]hept-3-yl)phenyl]sulfonyl}-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 1E for EXAMPLE 27G and4-(2,4-dioxo-3-azabicyclo[3.2.0]heptan-3-yl)benzenesulfonamide forEXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ11.87 (br s, 1H), 9.58 (br s, 1H), 7.93 (d, 2H), 7.71 (br s, 1H), 7.54(m, 7H), 7.35 (m, 5H), 7.10 (dd, 1H), 6.89 (d, 2H), 6.78 (dd, 1H), 6.42(s, 1H), 4.37 (br s, 1H), 3.78 (br s, 1H), 3.43 (m, 4H), 3.22, 3.00,2.85 (all v br s, total 6H), 2.62 (m, 2H), 2.18 (m, 2H).

Example 294-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl]sulfonyl}-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 1E for EXAMPLE 27G and4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)benzenesulfonamidefor EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ11.87 (br s, 1H), 11.20 (s, 1H), 9.58 (br s, 1H), 7.90 (d, 2H), 7.83 (d,2H), 7.50 (m, 5H), 7.32 (m, 5H), 7.08 (dd, 1H), 6.85 (d, 2H), 6.76 (dd,1H), 6.43 (s, 1H), 4.38 (br s, 1H), 3.80 (br s, 1H), 3.60 (m, 2H), 3.40(m, 2H), 3.21, 3.00, 2.84 (all br s, total 6H), 2.75 (dd, 1H), 2.28 (d,1H), 1.08 (d, 3H).

Example 304-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-(3,3-dimethyl-2-oxoazetidin-1-yl)phenyl]sulfonyl}-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 1E for EXAMPLE 27G and4-(3,3-dimethyl-2-oxoazetidin-1-yl)benzenesulfonamide for EXAMPLE 1F inEXAMPLE 27H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.62 (br s, 1H),9.58 (br s, 1H), 7.80 (d, 2H), 7.72 (br s, 1H), 7.50 (m, 5H), 7.40 (m,4H), 7.33 (m, 3H), 7.08 (dd, 1H), 6.85 (d, 2H), 6.76 (dd, 1H), 6.41 (s,1H), 4.38 (br s, 1H), 3.77 (br s, 1H), 3.58 (s, 2H), 3.45 (m, 2H), 3.21,3.00, 2.84 (all br s, total 6H), 1.32 (s, 6H).

Example 314-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-(4-nitro-2H-1,2,3-triazol-2-yl)phenyl]sulfonyl}-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 1E for EXAMPLE 27G and4-(4-nitro-2H-1,2,3-triazol-2-yl)benzenesulfonamide for EXAMPLE 1F inEXAMPLE 27H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.98 (br s, 1H),9.58 (br s, 1H), 9.11 (s, 1H), 8.21 (d, 2H), 8.05 (d, 2H), 7.70 (br s,1H), 7.50 (m, 5H), 7.39 (m, 2H), 7.30 (m, 1H), 7.24 (m, 2H), 7.00 (dd,1H), 6.82 (d, 2H), 6.78 (dd, 1H), 6.43 (s, 1H), 4.38 (br s, 1H), 3.77(br s, 1H), 3.45 (m, 2H), 3.21, 3.00, 2.84 (all br s, total 6H).

Example 324-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-phenoxy-N-{[2-(2-piperidin-1-ylethoxy)phenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 1E for EXAMPLE 27G and2-(2-(piperidin-1-yl)ethoxy)benzenesulfonamide for EXAMPLE 1F in EXAMPLE27H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.65 (br s, 1H), 9.77 (brs, 1H), 8.95 (br s, 1H), 7.80 (dd, 1H), 7.70 (br s, 1H), 7.68 (m, 1H),7.50 (m, 5H), 7.36 (m, 5H), 7.23 (d, 1H), 7.15 (m, 2H), 6.90 (d, 2H),6.78 (dd, 1H), 6.42 (s, 1H), 4.40 (m, 3H), 3.80 (br s, 1H), 3.40, 3.203.00, 2.90 (all v br m, total 13H), 1.63 (m, 5H), 1.27 (v br s, 1H).

Example 334-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[3-({[(1-ethylpyrrolidin-2-yl)methyl]amino}carbonyl)-4-methoxyphenyl]sulfonyl}-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 1E for EXAMPLE 27G andN-((1-ethylpyrrolidin-2-yl)methyl)-2-methoxy-5-sulfamoylbenzamide forEXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ11.75 (br s, 1H), 9.70 (br s, 1H), 9.25 (br s, 1H), 8.62 (t, 1H), 8.25(d, 1H), 7.90 (dd, 1H), 7.70 (br s, 1H), 7.50 (m, 5H), 7.40 (m, 2H),7.10 (m, 5H), 7.09 (dd, 1H), 6.85 (d, 2H), 6.76 (dd, 1H), 6.40 (s, 1H),4.39 (br s, 1H), 3.96 (s, 3H), 3.77 (br s, 1H), 3.60 (m, 4H), 3.55-2.80(envelope, 10H), 2.12 (m, 1H), 2.00 (m, 1H), 1.85 (m, 2H), 1.23 (t, 3H).

Example 344-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1-naphthyloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 34A methyl2-bromo-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting methyl2-bromo-4-fluorobenzoate for EXAMPLE 1C in EXAMPLE 1D.

Example 34B methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(naphthalen-1-yloxy)benzoate

This example was prepared by substituting EXAMPLE 34A for EXAMPLE 18Eand 1-naphthol for phenol in EXAMPLE 18F.

Example 34C4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(naphthalen-1-yloxy)benzoicacid

This example was prepared by substituting EXAMPLE 34B for EXAMPLE 1D inEXAMPLE 1E.

Example 34D4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1-naphthyloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 34C for EXAMPLE 27G inEXAMPLE 27H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.82 (br s, 1H),9.50 (br s, 1H), 8.58 (t, 1H), 8.29 (d, 1H), 8.18 (d, 1H), 7.85 (d, 1H),7.70 (br s, 1H), 7.50 (m, 8H), 7.38 (m, 4H), 7.20 (dd, 1H), 6.82 (m,2H), 6.55 (s, 1H), 6.45 (d, 1H), 4.38 (br s, 1H), 3.85 (dd, 2H), 3.78(br s, 1H), 3.27 (m, 6H), 3.22, 3.02, 2.85 (all br s, total 6H), 1.84(m, 1H), 1.60 (m, 2H), 1.29 (m, 2H).

Example 354-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(2-naphthyloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 35A 1-(difluoromethylsulfonyl)-2-fluorobenzene

This example was prepared by substituting EXAMPLE 34A for EXAMPLE 18Eand 2-naphthol for phenol in EXAMPLE 18F.

Example 35B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(naphthalen-2-yloxy)benzoicacid

This example was prepared by substituting EXAMPLE 35A for EXAMPLE 1D inEXAMPLE 1E.

Example 35C4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(2-naphthyloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 35B for EXAMPLE 27G inEXAMPLE 27H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.80 (br s, 1H),9.55 (br s, 1H), 8.50 (t, 1H), 8.39 (d, 1H), 7.83 (m, 2H), 7.69 (br s,1H), 7.64 (d, 1H), 7.50 (m, 6H), 7.37 (m, 5H), 7.18 (dd, 1H), 7.00 (d,1H), 6.81 (dd, 1H), 6.77 (d, 1H), 6.56 (d, 1H), 4.38 (br s, 1H), 3.85(dd, 2H), 3.78 (br s, 1H), 3.27 (m, 6H), 3.22, 3.02, 2.85 (all br s,total 6H), 1.84 (m, 1H), 1.60 (m, 2H), 1.29 (m, 2H).

Example 364-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(2-naphthyloxy)benzamide

This example was prepared by substituting EXAMPLE 35B for EXAMPLE 27Gand EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.80 (br s, 1H), 9.61 (br s, 2H), 8.57 (t, 1H),8.40 (d, 1H), 7.83 (m, 2H), 7.66 (m, 2H), 7.50 (m, 6H), 7.40 (m, 5H),7.18 (dd, 1H), 7.02 (d, 1H), 6.81 (d, 1H), 6.57 (s, 1H), 4.38 (br s,1H), 4.00 (m, 2H), 3.80 (br s, 1H), 3.40 (m, 8H), 3.30-2.80 (envelope,10H), 1.92 (m, 2H).

Example 374-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(2-naphthyloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 35B for EXAMPLE 27Gand EXAMPLE 163A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.82 (br s, 1H), 9.58 (br s, 1H), 8.03 (d, 1H),7.90 (m, 2H), 7.70 (d, 1H), 7.69 (br s, 1H), 7.65 (dd, 1H), 7.50 (m,7H), 7.36 (m, 3H), 7.18 (m, 2H), 7.05 (d, 1H), 6.81 (dd, 1H), 6.75 (d,1H), 6.56 (d, 1H), 4.38 (br s, 1H), 3.83 (dd, 2H), 3.78 (br s, 1H), 3.23(m, 4H), 3.22, 3.02, 2.85 (all br s, total 6H), 3.15 (m, 2H), 1.80 (m,1H), 1.55 (m, 2H), 1.22 (m, 2H).

Example 384-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(quinolin-7-yloxy)benzamideExample 38A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(quinolin-7-yloxy)benzoate

This example was prepared by substituting EXAMPLE 34A for EXAMPLE 18Eand quinolin-7-ol for phenol in EXAMPLE 18F.

Example 38B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(quinolin-7-yloxy)benzoicacid

This example was prepared by substituting EXAMPLE 38A for EXAMPLE 1D inEXAMPLE 1E.

Example 38C4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(quinolin-7-yloxy)benzamide

This example was prepared by substituting EXAMPLE 38B for EXAMPLE 27G inEXAMPLE 27H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.80 (d, 1H), 8.48(t, 1H), 8.35 (d, 1H), 8.32 (d, 1H), 7.90 (d, 1H), 7.74 (m, 1H), 7.59(m, 2H), 7.50 (m, 4H), 7.45 (dd, 1H), 7.38 (d, 2H), 7.30 (m, 2H), 6.95(d, 1H), 6.86 (dd, 1H), 6.83 (d, 1H), 6.71 (d, 1H), 4.38 (br s, 1H),3.85 (dd, 2H), 3.78 (br s, 1H), 3.30-2.80 (envelope, 12H), 1.84 (m, 1H),1.60 (m, 2H), 1.25 (m, 2H).

Example 394-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(quinolin-6-yloxy)benzamideExample 39A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(quinolin-6-yloxy)benzoate

This example was prepared by substituting EXAMPLE 34A for EXAMPLE 18Eand quinolin-6-ol for phenol in EXAMPLE 18F.

Example 39B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(quinolin-6-yloxy)benzoicacid

This example was prepared by substituting EXAMPLE 39A for EXAMPLE 1D inEXAMPLE 1E.

Example 39C4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(quinolin-6-yloxy)benzamide

This example was prepared by substituting EXAMPLE 39B for EXAMPLE 27G inEXAMPLE 27H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) 11.90 (br s, 1H),9.65 (br s, 1H), 8.80 (d, 1H), 8.46 (t, 1H), 8.35 (d, 1H), 7.90 (d, 1H),7.72 (m, 1H), 7.50 (m, 6H), 7.45 (dd, 1H), 7.37 (m, 4H), 7.02 (d, 1H),6.83 (dd, 1H), 6.79 (d, 1H), 6.63 (d, 1H), 4.38 (br s, 1H), 3.85 (dd,2H), 3.78 (br s, 1H), 3.40-2.80 (envelope 12H), 1.87 (m, 1H), 1.62 (m,2H), 1.26 (m, 2H).

Example 404-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 40A 1-(triisopropylsilyl)-1H-indol-5-ol

5-Benzyloxy-indole (1.0 g) was treated with NaH (135 mg) andtriisopropylsilyl chloride (1.0 g) in tetrahydrofuran for 1 hour,purified by flash chromatography (98/2 ethyl acetate/hexanes), thendebenzylated in ethanol (35 mL) using Pearlman's catalyst (0.19 g) and ahydrogen balloon.

Example 40B methyl2-(1H-indol-5-yloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 34A for EXAMPLE 18Eand EXAMPLE 40A for phenol in EXAMPLE 18F. In this example, the crudematerial from the ether formation was desilylated using tetrabutylammonium fluoride in tetrahydrofuran/water 95/5 prior to purification.

Example 40C2-(1H-indol-5-yloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 40B for EXAMPLE 1D inEXAMPLE 1E.

Example 40D4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 40C for EXAMPLE 27G inEXAMPLE 27H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.40 (br s, 1H),11.17 (s, 1H), 9.50 (v br s, 1H), 8.61 (t, 1H), 8.57 (d, 1H), 7.77 (dd,1H), 7.70 (br s, 1H), 7.50 (m, 5H), 7.36 (m, 5H), 7.10 (s, 1H), 7.08 (d,1H), 6.83 (dd, 1H), 6.69 (dd, 1H), 6.37 (m, 1H), 6.21 (d, 1H), 4.30 (brs, 1H), 3.84 (dd, 2H), 3.70 (br s, 1H), 3.30 (m, 6H), 3.20, 2.95, 2.80(all br s, total 6H), 1.86 (m, 1H), 1.60 (m, 2H), 1.25 (m, 2H).

Example 414-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(isoquinolin-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 41A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(isoquinolin-5-yloxy)benzoate

This example was prepared by substituting EXAMPLE 34A for EXAMPLE 18Eand isoquinolin-5-ol for phenol in EXAMPLE 18F.

Example 41B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(isoquinolin-5-yloxy)benzoicacid

This example was prepared by substituting EXAMPLE 41A for EXAMPLE 1D inEXAMPLE 1E.

Example 41C4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(isoquinolin-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 41B for EXAMPLE 27G inEXAMPLE 27H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.90 (br s, 1H),9.55 (v br s, 1H), 9.26 (s, 1H), 8.47 (m, 2H), 8.14 (d, 1H), 7.99 (d,1H), 7.65 (br s, 1H), 7.60 (d, 1H), 7.45 (m, 6H), 7.29 (m, 4H), 6.80 (m,2H), 6.60 (m, 2H), 4.38 (br s, 1H), 3.85 (dd, 2H), 3.78 (br s, 1H), 3.24(m, 6H), 3.22, 3.00, 2.85 (all br s, total 6H), 1.87 (m, 1H), 1.62 (m,2H), 1.26 (m, 2H).

Example 424-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(isoquinolin-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 41B for EXAMPLE 27Gand EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.90 (br s, 1H), 9.38 (v br s, 1H), 9.22 (s,1H), 8.54 (t, 1H), 8.45 (d, 1H), 8.16 (d, 1H), 7.96 (d, 1H), 7.62 (br s,1H), 7.56 (d, 1H), 7.50 (d, 1H), 7.45 (m, 5H), 7.29 (m, 4H), 6.80 (m,2H), 6.60 (m, 2H), 4.23 (br s, 1H), 3.78 (br s, 1H), 3.40 (m, 2H),3.35-2.80 (envelope, 8H), 3.08 (m, 2H), 2.72, 2.70 (both s, total 6H),1.87 (m, 2H).

Example 434-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(quinolin-6-yloxy)benzamide

This example was prepared by substituting EXAMPLE 39B for EXAMPLE 27Gand EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.96 (br s, 1H), 9.38 (v br s, 1H), 8.77 (dd,1H), 8.51 (t, 1H), 8.35 (d, 1H), 8.05 (d, 1H), 7.90 (d, 1H), 7.70 (br s,1H), 7.50 (m, 6H), 7.38 (m, 5H), 6.98 (d, 1H), 6.83 (dd, 1H), 6.79 (d,1H), 6.63 (d, 1H), 4.38 (br s, 1H), 3.78 (br s, 1H), 3.42 (m, 2H),3.35-2.80 (envelope, 8H), 3.15 (m, 2H), 2.81, 2.79 (both s, total 6H),1.93 (m, 2H).

Example 444-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 40C for EXAMPLE 27Gand EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.40 (br s, 1H), 11.18 (s, 1H), 9.30 (v br s,1H), 8.66 (t, 1H), 8.60 (d, 1H), 7.85 (dd, 1H), 7.52 (d, 1H), 7.50 (m,5H), 7.40 (m, 4H), 7.30 (br s, 1H), 7.14 (s, 1H), 7.10 (d, 1H), 6.84(dd, 1H), 6.67 (dd, 1H), 6.39 (m, 1H), 6.20 (s, 1H), 4.35 (br s, 1H),3.78 (br s, 1H), 3.40 (m, 2H), 3.35-2.80 (envelope, 8H), 3.10 (m, 2H),2.78, 2.76 (both s, total 6H), 1.95 (m, 2H).

Example 454-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 45A 1-(triisopropylsilyl)-1H-indol-4-ol

4-Benzyloxy-indole (1.0 g) was treated with NaH (135 mg) andtriisopropylsilyl chloride (1.0 g) in tetrahydrofuran for 1 hour,purified by flash chromatography (98/2 ethyl acetate/hexanes), thendebenzylated in ethanol (35 mL) using Pearlman's catalyst (0.19 g) and ahydrogen balloon.

Example 45B methyl2-(1H-indol-4-yloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 34A for EXAMPLE 18Eand EXAMPLE 45A for phenol in EXAMPLE 18F. Here the crude material fromthe ether formation was desilated using tetra-n-butylammonium fluoridein tetrahydrofuran/water 95/5 prior to purification.

Example 45C2-(1H-indol-4-yloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 45B for EXAMPLE 1D inEXAMPLE 1E.

Example 45D4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 45C for EXAMPLE 27G inEXAMPLE 27H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.50 (br s, 1H),11.24 (s, 1H), 9.50 (v br s, 1H), 8.61 (t, 1H), 8.47 (d, 1H), 7.70 (brs, 1H), 7.64 (dd, 1H), 7.50 (m, 5H), 7.30 (m, 4H), 7.15 (d, 2H), 7.04(d, 2H), 6.92 (dd, 1H), 6.75 (dd, 1H), 6.33 (m, 2H), 6.23 (s, 1H), 4.30(br s, 1H), 3.84 (dd, 2H), 3.70 (br s, 1H), 3.30 (m, 6H), 3.20, 2.95,2.80 (all br s, total 6H), 1.86 (m, 1H), 1.60 (m, 2H), 1.25 (m, 2H).

Example 464-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 45C for EXAMPLE 27Gand EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.50 (v br s, 1H), 11.24 (s, 1H), 9.30 (br s,1H), 8.66 (t, 1H), 8.53 (d, 1H), 7.85 (dd, 1H), 7.55 (d, 1H), 7.50 (m,5H), 7.39 (m, 2H), 7.30 (m, 2H), 7.148 (d, 1H), 7.10 (d, 1H), 6.96 (dd,1H), 6.72 (dd, 1H), 6.41 (d, 1H), 6.32 (s, 1H), 6.23 (s, 1H), 4.35 (brs, 1H), 3.78 (br s, 1H), 3.40 (m, 2H), 3.35-2.80 (envelope, 8H), 3.10(m, 2H), 2.78, 2.76 (both s, total 6H), 1.95 (m, 2H).

Example 474-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-6-yloxy)benzamideExample 47A 1-(triisopropylsilyl)-1H-indol-6-ol

6-Benzyloxy-indole (1.0 g) was treated with NaH (135 mg) andtriisopropylsilyl chloride (1.0 g) in tetrahydrofuran for 1 hour,purified by flash chromatography (98/2 ethyl acetate/hexanes), thendebenzylated in ethanol (35 mL) using Pearlman's catalyst (0.19 g) and ahydrogen balloon.

Example 47B methyl2-(1H-indol-6-yloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 34A for EXAMPLE 18Eand EXAMPLE 47A for phenol in EXAMPLE 18F. In this example, the crudematerial from the ether formation was desilated using tetrabutylammonium fluoride in tetrahydrofuran/water 95/5 prior to purification.

Example 47C2-(1H-indol-6-yloxy)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 47B for EXAMPLE 1D inEXAMPLE 1E.

Example 47D4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-6-yloxy)benzamide

This example was prepared by substituting EXAMPLE 47C for EXAMPLE 27Gand EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.50 (v br s, 1H), 11.00 (s, 1H), 9.38 (br s,1H), 8.64 (t, 1H), 8.58 (d, 1H), 7.75 (dd, 1H), 7.65 (br s, 1H), 7.55(d, 1H), 7.50 (m, 5H), 7.39 (m, 2H), 7.30 (m, 2H), 7.00 (d, 1H), 6.90(s, 1H), 6.70 (m, 2H), 6.42 (m, 1H), 6.30 (s, 1H), 4.35 (br s, 1H), 3.78(br s, 1H), 3.40 (m, 2H), 3.35-2.80 (envelope, 8H), 3.10 (m, 2H), 2.78,2.76 (both s, total 6H), 1.95 (m, 2H).

Example 484-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(isoquinolin-7-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 48A

This EXAMPLE was prepared by substituting EXAMPLE 34A for EXAMPLE 18Eand isoquinolin-7-ol for phenol in EXAMPLE 18F.

Example 48B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(isoquinolin-7-yloxy)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 48A for EXAMPLE 1D inEXAMPLE 1E.

Example 48C4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(isoquinolin-7-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 48B for EXAMPLE 27Gand EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.98 (v br s, 1H), 9.70 (v br s, 2H), 9.10 (s,1H), 8.56 (t, 1H), 8.42 (d, 1H), 8.13 (d, 1H), 7.93 (d, 1H), 7.81 (d,1H), 7.70 (br s, 1H), 7.60 (m, 2H), 7.50 (m, 5H), 7.40 (d, 2H), 7.35 (m,1H), 7.14 (d, 1H), 6.84 (m, 2H), 6.70 (d, 1H), 4.38 (br s, 1H), 4.00 (m,2H), 3.80 (br s, 1H), 3.40 (m, 4H), 3.30-2.80 (envelope, 10H), 3.20 (m,4H), 1.92 (m, 2H).

Example 494-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(isoquinolin-7-yloxy)benzamide

This example was prepared by substituting EXAMPLE 48B for EXAMPLE 27Gand EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.98 (v br s, 1H), 9.40 (br s, 2H), 9.10 (s,1H), 8.56 (t, 1H), 8.40 (d, 1H), 8.13 (d, 1H), 7.93 (d, 1H), 7.81 (d,1H), 7.70 (br s, 1H), 7.60 (m, 2H), 7.50 (m, 5H), 7.40 (d, 2H), 7.35 (m,1H), 7.14 (d, 1H), 6.84 (m, 2H), 6.70 (d, 1H), 4.38 (br s, 1H), 3.78 (brs, 1H), 3.42 (m, 2H), 3.35-2.80 (envelope, 8H), 3.15 (m, 2H), 2.81, 2.79(both s, total 6H), 1.93 (m, 2H).

Example 504-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 50A methyl2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 19D for EXAMPLE 34A inEXAMPLE 40B.

Example 50B2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 50A for EXAMPLE 1D inEXAMPLE 1E.

Example 50C4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 50B for EXAMPLE 27Gand EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.98 (br s, 1H), 11.20 (s, 1H), 9.70 (v br s,1H), 9.35 (v br s, 1H), 8.71 (t, 1H), 8.62 (d, 1H), 7.86 (dd, 1H), 7.54(d, 1H), 7.40 (m, 4H), 7.12 (m, 4H), 6.87 (dd, 1H), 6.70 (dd, 1H), 6.40(m, 1H), 6.20 (d, 1H), 3.98 (m, 2H), 3.50, 3.40, 3.30 (all m, total12H), 3.19 (m, 2H), 3.00 (m, 4H), 2.75 (br s, 2H), 2.23 (br m, 2H), 1.97(br m, 2H), 1.43 (br t, 2H), 0.98 (s, 6H).

Example 514-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 50B for EXAMPLE 27Gand EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.42 (br s, 1H), 11.20 (s, 1H), 9.40 (v br s,1H), 9.30 (v br s, 1H), 8.66 (t, 1H), 8.61 (d, 1H), 7.86 (dd, 1H), 7.54(d, 1H), 7.40 (m, 4H), 7.18 (d, 1H), 7.12 (m, 3H), 6.87 (dd, 1H), 6.70(dd, 1H), 6.40 (s, 1H), 6.20 (s, 1H), 3.60 (br s, 2H), 3.50 (m, 4H),3.35 (br s, 2H), 3.13 (m, 3H), 3.00 (br m, 2H), 2.78, 2.77 (both s,total 6H), 2.70 (br s, 1H), 2.12 (br m, 2H), 1.97 (m, 4H), 1.42 (br t,2H), 0.97 (s, 6H).

Example 524-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 27Gand EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.40 (br s, 1H), 11.20 (s, 1H), 9.60 (v br s,1H), 9.25 (v br s, 1H), 8.70 (t, 1H), 8.62 (d, 1H), 7.86 (dd, 1H), 7.54(d, 1H), 7.40 (m, 4H), 7.18 (d, 1H), 7.13 (d, 1H), 7.09 (d, 2H), 6.87(dd, 1H), 6.70 (dd, 1H), 6.40 (m, 1H), 6.20 (s, 1H), 3.98 (m, 2H), 3.50,3.40, 3.30 (all m, total 12H), 3.19 (m, 2H), 3.00 (m, 4H), 2.75 (br s,2H), 2.18 (br m, 2H), 2.00 (br m, 4H), 1.43 (br t, 2H), 0.96 (s, 6H).

Example 534-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 27Gand EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.41 (br s, 1H), 11.20 (s, 1H), 9.35 (v br s,2H), 8.66 (t, 1H), 8.62 (d, 1H), 7.86 (dd, 1H), 7.54 (d, 1H), 7.40 (m,4H), 7.18 (d, 1H), 7.13 (d, 1H), 7.09 (d, 2H), 6.87 (dd, 1H), 6.70 (dd,1H), 6.40 (m, 1H), 6.20 (s, 1H), 3.50 (m, 4H), 3.35 (br s, 2H), 3.13 (m,3H), 3.00 (br m, 2H), 2.78, 2.77 (both s, total 6H), 2.70 (br s, 1H),2.20 (br m, 2H), 2.00 (m, 2H), 1.93 (m, 2H), 1.42 (br t, 2H), 0.97 (s,6H).

Example 544-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 54A methyl2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 19D for EXAMPLE 34A inEXAMPLE 45B.

Example 54B2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 54A for EXAMPLE 1D inEXAMPLE 1E.

Example 54C4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 54B for EXAMPLE 27Gand EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.50 (br s, 1H), 11.27 (s, 1H), 9.60 (v br s,1H), 9.20 (v br s, 1H), 8.65 (t, 1H), 8.55 (d, 1H), 7.80 (dd, 1H), 7.57(d, 1H), 7.40 (d, 2H), 7.30 (dd, 1H), 7.12 (d, 2H), 7.10 (d, 2H), 7.00(dd, 1H), 6.73 (dd, 1H), 6.46 (d, 1H), 6.30 (s, 1H), 6.23 (m, 1H), 3.98(m, 2H), 3.60, 3.50, 3.40 (all m, total 12H), 3.19 (m, 2H), 3.00 (m,4H), 2.75 (br s, 2H), 2.23 (br m, 2H), 1.97 (br m, 4H), 1.43 (br t, 2H),0.98 (s, 6H).

Example 554-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 55A methyl2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 45A for phenol inEXAMPLE 18F. Here the crude material from the ether formation wasdesilated using tetrabutyl ammonium fluoride in tetrahydrofuran/water95/5 prior to purification.

Example 55B2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 55A for EXAMPLE 1D inEXAMPLE 1E.

Example 55C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 27Gand EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.50 (br s, 1H), 11.25 (s, 1H), 9.60 (v br s,1H), 9.20 (v br s, 1H), 8.65 (t, 1H), 8.55 (d, 1H), 7.80 (dd, 1H), 7.57(d, 1H), 7.40 (d, 2H), 7.30 (dd, 1H), 7.20 (d, 1H), 7.10 (m, 3H), 7.00(dd, 1H), 6.73 (dd, 1H), 6.46 (d, 1H), 6.30 (s, 1H), 6.23 (m, 1H), 3.98(m, 2H), 3.60, 3.50, 3.40 (all m, total 12H), 3.19 (m, 2H), 3.00 (m,4H), 2.75 (br s, 2H), 2.20 (br m, 2H), 2.00 (br m, 4H), 1.43 (br t, 2H),0.98 (s, 6H).

Example 564-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 54B for EXAMPLE 27Gand EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.55 (br s, 1H), 11.27 (s, 1H), 9.40 (v br s,1H), 9.35 (v br s, 1H), 8.65 (t, 1H), 8.55 (d, 1H), 7.79 (dd, 1H), 7.57(d, 1H), 7.40 (d, 2H), 7.30 (dd, 1H), 7.20 (d, 1H), 7.10 (m, 3H), 7.00(dd, 1H), 6.73 (dd, 1H), 6.46 (d, 1H), 6.30 (s, 1H), 6.23 (m, 1H), 3.50(m, 4H), 3.35 (br s, 2H), 3.13 (m, 3H), 3.00 (br m, 2H), 2.78, 2.77(both s, total 6H), 2.70 (br s, 1H), 2.22 (br m, 2H), 1.97 (m, 2H), 1.93(m, 2H), 1.42 (br t, 2H), 0.97 (s, 6H).

Example 574-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 27Gand EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.50 (br s, 1H), 11.25 (s, 1H), 9.60 (v br s,1H), 9.20 (v br s, 1H), 8.65 (t, 1H), 8.55 (d, 1H), 7.79 (dd, 1H), 7.57(d, 1H), 7.40 (d, 2H), 7.30 (dd, 1H), 7.20 (d, 1H), 7.10 (m, 3H), 7.00(dd, 1H), 6.73 (dd, 1H), 6.46 (d, 1H), 6.30 (s, 1H), 6.23 (m, 1H), 3.50(m, 4H), 3.35 (br s, 2H), 3.13 (m, 3H), 3.00 (br m, 2H), 2.78, 2.77(both s, total 6H), 2.70 (br s, 1H), 2.20 (br m, 2H), 2.00 (m, 2H), 1.93(m, 2H), 1.42 (br t, 2H), 0.97 (s, 6H).

Example 584-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 45C for EXAMPLE 27Gand EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.50 (br s, 1H), 11.24 (s, 1H), 9.50 (v br s,1H), 8.67 (t, 1H), 8.52 (d, 1H), 7.78 (dd, 1H), 7.70 (br s, 1H), 7.55(d, 1H), 7.50 (m, 4H), 7.38 (d, 2H), 7.30 (dd, 2H), 7.18 (d, 1H), 7.08(d, 1H), 6.96 (dd, 1H), 6.75 (dd, 1H), 6.40 (d, 1H), 6.33 (s, 1H), 6.23(s, 1H), 4.38 (br s, 1H), 4.00 (m, 2H), 3.80 (br s, 1H), 3.40 (m, 4H),3.30-2.80 (envelope, 10H), 3.20 (m, 4H), 1.95 (m, 2H).

Example 594-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 40C for EXAMPLE 27Gand EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.40 (br s, 1H), 11.19 (s, 1H), 9.60 (v br s,1H), 8.69 (t, 1H), 8.60 (d, 1H), 7.83 (dd, 1H), 7.65 (br s, 1H), 7.50(m, 5H), 7.38 (m, 5H), 7.12 (m, 2H), 6.83 (dd, 1H), 6.69 (dd, 1H), 6.39(m, 1H), 6.20 (d, 1H), 4.38 (br s, 1H), 4.00 (m, 2H), 3.80 (br s, 1H),3.40 (m, 4H), 3.30-2.80 (envelope, 10H), 3.20 (m, 4H), 1.96 (m, 2H).

Example 604-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-methoxyphenyl)sulfonyl]-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 1E for EXAMPLE 27G and4-methoxybenzenesulfonamide for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (500MHz, dimethylsulfoxide-d₆) δ 11.57 (s, 1H), 7.74 (d, 2H), 7.50 (m, 5H),7.35 (m, 6H), 7.10 (t, 1H), 7.02 (m, 2H), 6.87 (d, 2H), 6.75 (dd, 1H),6.41 (s, 1H), 4.36 (m, 2H), 3.83 (s, 3H), 3.76 (m, 2H), 3.23 (m, 2H),3.01 (m, 2H), 2.84 (m, 2H).

Example 614-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-methylphenyl)sulfonyl]-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 1E for EXAMPLE 27G and4-methylbenzenesulfonamide for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (500MHz, dimethylsulfoxide-d₆) δ 11.64 (s, 1H), 7.68 (d, 2H), 7.50 (m, 5H),7.38 (m, 2H), 7.32 (m, 6H), 7.11 (t, 1H), 6.87 (d, 2H), 6.75 (dd, 1H),6.41 (s, 1H), 4.36 (m, 2H), 3.76 (m, 2H), 3.23 (m, 2H), 3.01 (m, 2H),2.84 (m, 2H), 2.37 (s, 3H).

Example 624-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 40C for EXAMPLE 27Gand EXAMPLE 163A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.46 (s, 1H), 11.16 (s, 1H), 8.17 (d, 1H), 7.88(dd, 1H), 7.68 (br s, 1H), 7.50 (m, 5H), 7.36 (m, 6H), 7.13 (s, 1H),7.03 (d, 1H), 6.84 (dd, 1H), 6.68 (dd, 1H), 6.39 (m, 1H), 6.21 (br s,1H), 4.32 (s, 2H), 3.84 (dd, 2H), 3.25 (m, 7H), 2.93 (m, 4H), 1.84 (m,2H), 1.54 (m, 2H), 1.24 (m, 2H).

Example 634-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 45C for EXAMPLE 27Gand EXAMPLE 163A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.58 (s, 1H), 11.27 (s, 1H), 8.12 (d, 1H), 7.71(m, 2H), 7.52 (m, 5H), 7.32 (m, 5H), 7.18 (d, 1H), 6.96 (m, 2H), 6.74(dd, 1H), 6.36 (m, 2H), 6.26 (m, 1H), 4.32 (s, 2H), 3.84 (dd, 2H), 3.25(m, 7H), 2.93 (m, 4H), 1.84 (m, 2H), 1.54 (m, 2H), 1.24 (m, 2H).

Example 644-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-{[3-(dimethylamino)propyl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 40C and EXAMPLE 170Afor EXAMPLE 27G and EXAMPLE 1F respectively, in EXAMPLE 27H. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 11.46 (br s, 1H), 11.18 (s, 1H), 8.21 (d,1H), 7.98 (dd, 1H), 7.50 (m, 6H), 7.41 (m, 5H), 7.29 (br s, 1H), 7.17(s, 1H), 7.08 (d, 1H), 6.84 (dd, 1H), 6.68 (dd, 1H), 6.40 (m, 1H), 6.18(br s, 1H), 4.32 (br s, 2H), 3.59 (m, 4H), 3.25 (m, 2H), 3.05 (m, 4H),2.90 (m, 2H), 2.77 (d, 6H), 1.88 (m, 2H).

Example 654-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamideExample 65A4-(3-morpholinopropylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

This example was prepared by substituting EXAMPLE 159C and3-morpholinopropan-1-amine for 4-fluoro-3-nitrobenzenesulfonamide and(tetrahydropyran-4-yl)methylamine respectively, in EXAMPLE 1F.

Example 65B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 40C and EXAMPLE 65Afor EXAMPLE 27G and EXAMPLE 1F respectively, in EXAMPLE 27H. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 11.46 (br s, 1H), 11.18 (s, 1H), 8.18 (d,1H), 7.91 (m, 1H), 7.50 (m, 6H), 7.41 (m, 5H), 7.30 (m, 1H), 7.19 (d,1H), 7.08 (m, 1H), 6.99 (m, 1H), 6.72 (dd, 1H), 6.48 (br s, 1H), 6.25(m, 1H), 4.29 (br s, 2H), 4.01 (m, 2H), 3.59 (m, 2H), 3.41 (m, 4H), 3.05(m, 10H), 2.58 (m, 2H), 1.91 (m, 2H).

Example 66N-[(3-{[chloro(difluoro)methyl]sulfonyl}-4-{[3-(dimethylamino)propyl]amino}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamideExample 66A (difluoromethyl)(2-fluorophenyl)sulfane

Powdered NaOH (31.2 g), tris(2-(2-methoxyethoxy)ethyl)amine (5 mL) and2-fluorobenzene thiol (33.6 mL) in benzene (400 mL) was saturated withchlorodifluoromethane, stirred at 80° C. for 30 minutes and filteredthrough diatomaceous earth (Celite®). The filtrate was washed withsaturated NaHCO₃ and the water layer was extracted with diethyl ether.The extracts were combined and dried (MgSO₄), filtered and concentrated.

Example 66B 1-(difluoromethylsulfonyl)-2-fluorobenzene

EXAMPLE 66A (46 g) in 1:1:2 CCl₄/CH₃CN/water (1.2 L) at 25° C. wastreated with NaIO₄ (164.6 g) and RuCl₃.xH₂O (534 mg), stirred for 18hours, diluted with dichloromethane and filtered through diatomaceousearth (Celite®). The filtrate was washed with saturated NaHCO₃ and dried(Na₂SO₄), filtered and concentrated. The concentrate was filteredthrough silica gel.

Example 66C 1-(chlorodifluoromethylsulfonyl)-2-fluorobenzene

EXAMPLE 66B (25 g) and N-chlorosuccinimide (17.55 g) in tetrahydrofuran(690 mL) at −78° C. was treated with lithium hexamethyldisilazide (178.5mL) over 1 hour, stirred for 1 hour and quenched with ammonium chloride.The mixture was extracted with ethyl acetate, and the extract was washedwith brine and dried (MgSO₄), filtered and concentrated. The concentratewas chromatographed on silica gel with 0-5% ethyl acetate/hexanes.

Example 66D 3-(chlorodifluoromethylsulfonyl)-4-fluorobenzene-1-sulfonylchloride

EXAMPLE 66C (44 g) in chlorosulfonic acid (36.7 mL) at 120° C. wasstirred for 18 hours, cooled to 25° C., pipetted onto crushed ice andextracted with ethyl acetate. The extract was washed with water andbrine and dried (MgSO₄), filtered and concentrated.

Example 66E 3-(chlorodifluoromethylsulfonyl)-4-fluorobenzenesulfonamide

EXAMPLE 66D (22 g) in isopropanol (690 mL) at −78° C. was treated withaqueous ammonia (90 mL) over 1 hour, stirred for another hour, quenchedwith 6M HCl (300 mL), warmed to 25° C. and concentrated. The concentratewas mixed with water and extracted with ethyl acetate. The extract wasdried (MgSO₄), filtered and concentrated. The concentrate wasrecrystallized from hexanes/ethyl acetate.

Example 66F3-(chlorodifluoromethylsulfonyl)-4-(3-(dimethylamino)propylamino)benzenesulfonamide

This example was prepared by substituting EXAMPLE 66E andN,N-dimethylpropane-1,3-diamine for 4-fluoro-3-nitrobenzenesulfonamideand (tetrahydropyran-4-yl)methylamine respectively, in EXAMPLE 1F.

Example 66GN-[(3-{[chloro(difluoro)methyl]sulfonyl}-4-{[3-(dimethylamino)propyl]amino}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 54B and EXAMPLE 66Ffor EXAMPLE 27G and EXAMPLE 1F respectively, in EXAMPLE 27H. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 11.20 (s, 1H), 8.28 (m, 1H), 7.99 (m, 1H),7.55 (m, 2H), 7.38 (m, 2H), 7.21 (m, 3H), 7.09 (d, 2H), 6.98 (m, 1H),6.71 (m, 1H), 6.41 (m, 2H), 6.21 (m, 1H), 3.57 (m, 2H), 3.28 (m, 4H),2.84 (m, 6H), 2.67 (m, 5H), 2.19 (m, 2H), 2.02 (m, 2H), 1.77 (br s, 2H),1.61 (m, 2H), 1.46 (m, 2H), 0.94 (s, 6H).

Example 67N-[(3-{[chloro(difluoro)methyl]sulfonyl}-4-{[3-(dimethylamino)propyl]amino}phenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 26C and EXAMPLE 66Ffor EXAMPLE 27G and EXAMPLE 1F respectively, in EXAMPLE 27H. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 11.20 (s, 1H), 8.28 (m, 1H), 8.05 (m, 1H),7.99 (m, 1H), 7.55 (m, 2H), 7.38 (m, 2H), 7.21 (m, 3H), 7.09 (d, 2H),6.98 (m, 1H), 6.71 (m, 1H), 6.41 (m, 2H), 6.21 (m, 1H), 3.57 (m, 2H),3.28 (m, 4H), 3.05 (m, 2H), 2.96 (m, 2H), 2.88 (s, 3H), 2.78 (m, 2H),2.68 (m, 3H), 2.19 (m, 2H), 2.01 (br s, 2H), 1.72 (m, 2H), 1.45 (m, 2H),0.93 (s, 6H).

Example 682-(1H-indol-4-yloxy)-4-(4-{[2-(4-methoxyphenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamideExample 68A (2-bromo-4,4-dimethylcyclohex-1-enyl)methanol

N,N-dimethylformamide (18.41 ml) was taken up in chloroform (64 ml) andthe resulting solution was cooled in an ice bath. Phosphorus tribromide(20.18 ml) was added dropwise over 15 minutes. The resulting suspensionwas then heated to 70° C. for 30 minutes. A solution of3,3-dimethylcyclohexanone (10 g) in chloroform (21 ml) was addeddropwise over 30 minutes. The mixture was stirred at 70° C. for another2 hours. The mixture was then allowed to cool to room temperature. Thesolution was cautiously poured over ice. Solid sodium bicarbonate wasadded to neutralize acid. The mixture was extracted three times withether, and the extracts were washed with water and brine and dried(MgSO₄). The solvent was removed under vacuum, and the crude materialwas flushed through a silica plug with ether as the eluent. Afterconcentration, the crude material was dissolved in methanol. Sodiumborohydride (1.757 g) was added cautiously. The resulting mixture wasstirred at room temperature overnight, and diluted with ethyl acetate.The mixture was washed with water and brine and dried (MgSO₄). Thesolvent was removed under vacuum, and the residue was purified by flashchromatography eluting with 20% ethyl acetate in hexanes to 100% ethylacetate.

Example 68B methyl 2-(1H-indol-4-yloxy)-4-(piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 24F and piperazine forEXAMPLE 1C and EXAMPLE 1B respectively, in EXAMPLE 1D.

Example 68C methyl2-(1H-indol-4-yloxy)-4-(4-((2-bromo-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 68A and EXAMPLE 68Bfor EXAMPLE 18C and EXAMPLE 18D respectively, in EXAMPLE 18E.

Example 68D methyl2-(1H-indol-4-yloxy)-4-(4-((2-(4-methoxyphenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

EXAMPLE 68C (142 mg), 4-methoxyphenylboronic acid (45.6 mg),bis(triphenylphosphine)palladium(II) dichloride (8.7 mg), and cesiumfluoride (114 mg) were combined in dimethoxyethane (0.9 mL) and methanol(0.4 mL) and heated to 90° C. for 2 hours. The reaction mixture wasdiluted with ethyl acetate and poured into water. The organic layer waswashed with water and with brine, dried (MgSO₄), filtered, andconcentrated. The resulting solid was triturated with methanol, andfiltered.

Example 68E2-(1H-indol-4-yloxy)-4-(4-((2-(4-methoxyphenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 68D for EXAMPLE 1D inEXAMPLE 1E.

Example 68F 3-nitro-4-(3-(pyrrolidin-1-yl)propylamino)benzenesulfonamide

This example was prepared by substituting3-(pyrrolidin-1-yl)propan-1-amine for (tetrahydropyran-4-yl)methylaminein EXAMPLE 1F.

Example 68G2-(1H-indol-4-yloxy)-4-(4-{[2-(4-methoxyphenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 68E and EXAMPLE 68Ffor EXAMPLE 27G and EXAMPLE 1F respectively, in EXAMPLE 27H. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 11.56 (brs, 1H), 11.26 (s, 1H), 8.66 (t,1H), 8.53 (d, 1H), 7.78 (dd, 1H), 7.56 (d, 1H), 7.29 (t, 1H), 7.19 (d,1H), 7.10 (d, 1H), 6.98 (m, 3H), 6.88 (m, 2H), 6.74 (m, 1H), 6.43 (d,1H), 6.36 (br s, 1H), 6.23 (m, 1H), 3.73 (s, 3H), 3.62 (m, 2H), 3.52 (m,4H), 3.22 (m, 4H), 2.99 (m, 4H), 2.18 (m, 2H), 1.99 (m, 6H), 1.84 (m,2H), 1.45 (m, 2H), 1.23 (m, 2H), 0.94 (s, 6H).

Example 694-[4-({4,4-dimethyl-2-[4-(trifluoromethyl)phenyl]cyclohex-1-en-1-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamideExample 69A methyl2-(1H-indol-4-yloxy)-4-(4-((4,4-dimethyl-2-(4-(trifluoromethyl)phenyl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting4-(trifluoromethyl)phenylboronic acid for 4-methoxyphenylboronic acid inEXAMPLE 68D.

Example 69B2-(1H-indol-4-yloxy)-4-(4-((4,4-dimethyl-2-(4-(trifluoromethyl)phenyl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 69A for EXAMPLE 1D inEXAMPLE 1E.

Example 69C4-[4-({4,4-dimethyl-2-[4-(trifluoromethyl)phenyl]cyclohex-1-en-1-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 69B and EXAMPLE 68Ffor EXAMPLE 27G and EXAMPLE 1F respectively, in EXAMPLE 27H. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 11.55 (br s, 1H), 11.26 (s, 1H), 8.66 (t,1H), 8.53 (d, 1H), 7.78 (m, 1H), 7.67 (m, 2H), 7.56 (m, 1H), 7.29 (m,3H), 7.19 (d, 1H), 7.10 (d, 1H), 6.98 (m, 1H), 6.72 (m, 1H), 6.46 (m,1H), 6.36 (br s, 1H), 6.23 (m, 1H), 3.62 (m, 4H), 3.52 (m, 4H), 3.18 (m,4H), 3.02 (m, 4H), 2.19 (m, 2H), 2.02 (m, 6H), 1.82 (m, 2H), 1.47 (m,2H), 0.94 (s, 6H).

Example 704-[4-({4,4-dimethyl-2-[4-(trifluoromethoxy)phenyl]cyclohex-1-en-1-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamideExample 70A methyl2-(1H-indol-4-yloxy)-4-(4-((4,4-dimethyl-2-(4-(trifluoromethoxy)phenyl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting4-(trifluoromethoxy)phenylboronic acid for 4-methoxyphenylboronic acidin EXAMPLE 68D.

Example 70B2-(1H-indol-4-yloxy)-4-(4-((4,4-dimethyl-2-(4-(trifluoromethoxy)phenyl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 70A for EXAMPLE 1D inEXAMPLE 1E.

Example 70C4-[4-({4,4-dimethyl-2-[4-(trifluoromethoxy)phenyl]cyclohex-1-en-1-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 70B and EXAMPLE 68Ffor EXAMPLE 27G and EXAMPLE 1F respectively, in EXAMPLE 27H. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 11.56 (br s, 1H), 11.26 (s, 1H), 8.66 (t,1H), 8.54 (d, 1H), 7.80 (m, 1H), 7.63 (m, 2H), 7.56 (m, 3H), 7.29 (m,2H), 7.19 (m, 2H), 6.98 (m, 1H), 6.72 (m, 1H), 6.46 (m, 1H), 6.23 (m,1H), 3.62 (m, 4H), 3.52 (m, 4H), 3.18 (m, 4H), 3.02 (m, 4H), 2.19 (m,2H), 2.02 (m, 6H), 1.82 (m, 2H), 1.47 (m, 2H), 0.94 (s, 6H).

Example 714-[4-({4,4-dimethyl-2-[3-(trifluoromethyl)phenyl]cyclohex-1-en-1-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamideExample 71A methyl2-(1H-indol-4-yloxy)-4-(4-((4,4-dimethyl-2-(3-(trifluoromethyl)phenyl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting3-(trifluoromethyl)phenylboronic acid for 4-methoxyphenylboronic acid inEXAMPLE 68D.

Example 71B2-(1H-indol-4-yloxy)-4-(4-((4,4-dimethyl-2-(3-(trifluoromethyl)phenyl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 71A for EXAMPLE 1D inEXAMPLE 1E.

Example 71C4-[4-({4,4-dimethyl-2-[3-(trifluoromethyl)phenyl]cyclohex-1-en-1-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 71B and EXAMPLE 68Ffor EXAMPLE 27G and EXAMPLE 1F respectively, in EXAMPLE 27H. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 11.55 (br s, 1H), 11.26 (s, 1H), 8.65 (t,1H), 8.54 (d, 1H), 7.80 (dd, 1H), 7.63 (m, 2H), 7.56 (m, 3H), 7.38 (m,2H), 7.29 (t, 1H), 7.19 (d, 1H), 7.11 (d, 1H), 6.98 (t, 1H), 6.72 (m,1H), 6.46 (m, 1H), 6.31 (m, 1H), 6.23 (m, 1H), 3.58 (m, 7H), 3.18 (m,4H), 3.02 (m, 4H), 2.19 (m, 3H), 2.02 (m, 6H), 1.82 (m, 2H), 1.47 (m,2H), 0.96 (s, 6H).

Example 724-(4-{[2-(3-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamideExample 72A methyl2-(1H-indol-4-yloxy)-4-(4-((2-(3-fluorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting 3-fluorophenylboronic acid for4-methoxyphenylboronic acid in EXAMPLE 68D.

Example 72B2-(1H-indol-4-yloxy)-4-(4-((2-(3-fluorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 72A for EXAMPLE 1D inEXAMPLE 1E.

Example 72C4-(4-{[2-(3-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 72B and EXAMPLE 68Ffor EXAMPLE 27G and EXAMPLE 1F respectively, in EXAMPLE 27H. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 11.55 (br s, 1H), 11.26 (s, 1H), 8.65 (t,1H), 8.54 (d, 1H), 7.80 (m, 1H), 7.63 (m, 2H), 7.56 (m, 3H), 7.38 (m,2H), 7.29 (t, 1H), 7.19 (d, 1H), 7.11 (d, 1H), 6.98 (m, 1H), 6.72 (m,1H), 6.46 (m, 1H), 6.31 (m, 1H), 6.23 (m, 1H), 3.58 (m, 7H), 3.18 (m,4H), 3.02 (m, 4H), 2.19 (m, 3H), 2.02 (m, 6H), 1.82 (m, 2H), 1.47 (m,2H), 0.96 (s, 6H).

Example 734-(4-{[2-(4-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamideExample 73A methyl2-(1H-indol-4-yloxy)-4-(4-((2-(4-fluorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting 4-fluorophenylboronic acid for4-methoxyphenylboronic acid in EXAMPLE 68D.

Example 73B2-(1H-indol-4-yloxy)-4-(4-((2-(4-fluorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 73A for EXAMPLE 1D inEXAMPLE 1E.

Example 73C4-(4-{[2-(4-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 73B and EXAMPLE 68Ffor EXAMPLE 27G and EXAMPLE 1F respectively, in EXAMPLE 27H. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 11.56 (br s, 1H), 11.26 (s, 1H), 8.66 (t,1H), 8.54 (d, 1H), 7.80 (m, 1H), 7.63 (m, 2H), 7.56 (m, 3H), 7.29 (m,2H), 7.19 (m, 2H), 6.98 (m, 1H), 6.72 (m, 1H), 6.46 (m, 1H), 6.23 (m,1H), 3.62 (m, 4H), 3.52 (m, 4H), 3.18 (m, 4H), 3.02 (m, 4H), 2.19 (m,2H), 2.02 (m, 6H), 1.82 (m, 2H), 1.47 (m, 2H), 0.94 (s, 6H).

Example 74N-({3-{[chloro(difluoro)methyl]sulfonyl}-4-[(1-methylpiperidin-4-yl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamideExample 74A3-(chlorodifluoromethylsulfonyl)-4-(1-methylpiperidin-4-ylamino)benzenesulfonamide

This example was prepared by substituting EXAMPLE 66E and1-methylpiperidin-4-amine for 4-fluoro-3-nitrobenzenesulfonamide and(tetrahydropyran-4-yl)methylamine respectively, in EXAMPLE 1F.

Example 74BN-({3-{[chloro(difluoro)methyl]sulfonyl}-4-[(1-methylpiperidin-4-yl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 26C and EXAMPLE 74Afor EXAMPLE 1E and EXAMPLE 1F respectively, in EXAMPLE 1G. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 11.07 (s, 1H), 8.11 (d, 1H), 7.89 (dd, 1H),7.50 (d, 1H), 7.34 (m, 4H), 7.05 (m, 3H), 6.96 (d, 1H), 6.78 (dd, 1H),6.60 (m, 2H), 6.36 (s, 1H), 6.13 (d, 1H), 3.67 (m, 1H), 2.97 (m, 6H),2.71 (s, 2H), 2.59 (m, 2H), 2.46 (s, 3H), 2.16 (m, 6H), 1.98 (m, 4H),1.55 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 754-(4-{[2-(4-chlorophenyl)cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 75A methyl2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 149D and EXAMPLE 150Afor 4′-chlorobiphenyl-2-carboxaldehyde andtert-butylpiperazine-1-carboxylate respectively, in EXAMPLE 1A.

Example 75B2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 75A for EXAMPLE 1D inEXAMPLE 1E.

Example 75C4-(4-{[2-(4-chlorophenyl)cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 75B and EXAMPLE 21Afor EXAMPLE 1E and EXAMPLE 1F respectively, in EXAMPLE 1G. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 11.07 (s, 1H), 8.52 (d, 1H), 8.12 (d, 1H),7.79 (dd, 1H), 7.52 (d, 1H), 7.34 (m, 4H), 7.05 (m, 4H), 6.79 (dd, 1H),6.59 (dd, 1H), 6.36 (s, 1H), 6.13 (d, 1H), 3.72 (m, 1H), 2.97 (m, 6H),2.69 (s, 2H), 2.59 (m, 2H), 2.46 (s, 3H), 2.16 (m, 6H), 2.11 (m, 2H),1.98 (m, 2H), 1.70 (m, 2H), 1.62 (m, 4H).

Example 764-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamideExample 76A4-(1-methylpiperidin-4-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

This example was prepared by substituting EXAMPLE 159C and1-methylpiperidin-4-amine for 4-fluoro-3-nitrobenzenesulfonamide and(tetrahydropyran-4-yl)methylamine respectively, in EXAMPLE 1F.

Example 76B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 26C and EXAMPLE 76Afor EXAMPLE 1E and EXAMPLE 1F respectively, in EXAMPLE 1G. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 11.08 (s, 1H), 8.11 (d, 1H), 7.89 (dd, 1H),7.50 (d, 1H), 7.34 (m, 4H), 7.05 (m, 3H), 6.98 (d, 1H), 6.78 (dd, 1H),6.60 (m, 2H), 6.36 (t, 1H), 6.13 (d, 1H), 3.67 (br s, 1H), 2.97 (m, 6H),2.71 (s, 3H), 2.63 (m, 1H), 2.47 (s, 3H), 2.17 (m, 6H), 1.98 (m, 4H),1.60 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 774-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(phenoxymethyl)benzamideExample 77A5-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)isobenzofuran-1(3H)-one

5-bromoisobenzofuran-1(3H)-one (400 mg), EXAMPLE 1B (646 mg), andpotassium phosphate tribasic (558 mg) were added to 1,2-dimethoxyethane(10 mL). The solution was degassed under vacuum and flushed withnitrogen three times. Tris(dibenzylideneacetone)dipalladium(0) (51.6 mg)and 2-(di-tert-butylphosphino)biphenyl (67.2 mg) were added and thesolution was heated to 80° C. for 16 hours. The solution was cooled,filtered, concentrated, and purified by flash column chromatography onsilica gel with 30% ethyl acetate in hexanes.

Example 77B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(hydroxymethyl)benzoicacid

EXAMPLE 77A (256 mg) and lithium hydroxide monohydrate (154 mg) wereadded to 1,4-dioxane (4 mL) and water (1 mL). The solution was heated to65° C. for 16 hours, cooled, concentrated under vacuum, and purified byflash column chromatography on silica gel with ethyl acetate. Thesolution was subsequently dried with anhydrous sodium sulfate to affordcrude product of sufficient purity for subsequent use.

Example 77C methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(hydroxymethyl)benzoate

Trimethylsilyldiazomethane (2M solution in diethyl ether, 0.214 mL) wasadded to EXAMPLE 77B (170 mg) dissolved in ethyl acetate (2 mL) andmethanol (2 mL). The solution was mixed for 5 minutes after which thesolvent was removed under vacuum to afford crude product of sufficientpurity for subsequent use.

Example 77D methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenoxymethyl)benzoate

Triphenylphosphine (93 mg) was added to tetrahydrofuran (3 mL) andcooled to 0° C. Diethylazodicarboxylate (40% solution, 0.161 mL) wasadded, and the solution was stirred at 0° C. for 15 minutes. Phenol(33.3 mg) and EXAMPLE 77C (145 mg) were added, and the solution wasallowed to warm to room temperature and mix for 16 hours. The solutionwas concentrated on vacuum and purified by flash column chromatographyon silica gel with 30% ethyl acetate (hexanes) increasing to 50% ethylacetate (hexanes).

Example 77E4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenoxymethyl)benzoicacid

This example was prepared by substituting EXAMPLE 77D for EXAMPLE 77A inEXAMPLE 77B.

Example 77F

This example was prepared by substituting EXAMPLE 77E for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.52 (m, 2H), 7.88(dd, 1H), 7.84 (d, 1H), 7.50 (m, 2H), 7.48 (s, 3H), 7.37 (m, 2H),7.26-7.10 (m, 4H), 7.01 (s, 1H), 6.87 (t, 1H), 6.83-6.75 (m, 3H), 5.22(broad s, 2H), 3.84 (dd, 2H), 3.41-3.10 (m, 10H), 2.39 (broad s, 4H),1.89 (m, 1H), 1.60 (m, 2H), 1.32-1.18 (m, 2H).

Example 784-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morpholin-4-ylpropyl)amino]phenyl}sulfonyl)-2-phenoxybenzamideExample 78A N-(4-sulfamoylphenyl)acrylamide

4-aminobenzenesulfonamide (1.00 g) and pyridine (1.41 mL) were added to1,4-dioxane (30 mL). Acryloyl chloride (0.49 mL) was added dropwise andthe solution was stirred for 3 hours at room temperature. 1M HCl wasadded, and the solution extracted with ethyl acetate. The extracts weredried using brine and anhydrous sodium sulfate and the solvent wasremoved to afford crude product of sufficient purity for subsequent use.

Example 78B 3-morpholino-N-(4-sulfamoylphenyl)propanamide

EXAMPLE 78A (359 mg) and morpholine (1.38 mL) were added to acetonitrile(10 mL) and N,N-dimethylformamide (1 mL) and mixed at room temperaturefor 16 hours. The solution was concentrated on vacuum, and purified byflash column chromatography on silica gel with 5% methanol indichloromethane.

Example 78C 4-(3-morpholinopropylamino)benzenesulfonamide

EXAMPLE 78B (268 mg) was added to tetrahydrofuran (4 mL). Borane (1M intetrahydrofuran, 4.28 mL) was added slowly, and the solution was mixedat room temperature for 16 hours. The reaction was quenched slowly withmethanol. N,N-diisopropylethylamine resin (3.42 mmol amine) was addedand the solution was mixed at room temperature for 15 minutes. Thesolution was filtered, concentrated on vacuum, and purified by flashcolumn chromatography on silica gel with 10% methanol in ethyl acetate.

Example 78D4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morpholin-4-ylpropyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 78C for EXAMPLE 1F inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 10.98 (broad s,1H), 7.51-7.44 (m, 9H), 7.40-7.31 (m, 3H), 7.26-7.21 (m, 1H), 7.13 (tt,1H), 6.94 (dd, 2H), 6.75 (dd, 1H), 6.66 (t, 1H), 6.54 (d, 2H), 6.32 (d,1H), 3.57 (t, 4H), 3.35 (m, 2H), 3.16-3.04 (m, 6H), 2.35 (m, 10H), 1.60(m, 2H).

Example 794-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(pyridin-3-yloxy)benzamideExample 79A methyl 4-bromo-2-fluorobenzoate

4-Bromo-2-fluorobenzoic acid (5.00 g) was added to ethyl acetate (35 mL)and methanol (35 mL). Trimethylsilyldiazomethane (2M solution in diethylether, 12.56 mL) was added slowly and the solution was mixed at roomtemperature for 30 minutes. The solvent was removed under vacuum, andthe crude material was dissolved in ethyl acetate. The solution wasextracted with 0.5M sodium hydroxide and dried with brine then anhydroussodium sulfate. After filtration, the solvent was removed under vacuumto afford crude product of sufficient purity for subsequent use.

Example 79B methyl 4-bromo-2-(pyridin-3-yloxy)benzoate

EXAMPLE 79A (500 mg), pyridine-3-ol (204 mg), and potassium carbonate(385 mg) were added to N,N-dimethylacetamide (18 mL) and the mixture washeated to 145° C. for 2 hours and then at 130° C. for 16 hours. Thesolution was cooled, added to water (100 mL), extracted with 70% ethylacetate in hexanes, and dried with anhydrous sodium sulfate. Afterfiltration, the solution was concentrated under vacuum and purified byflash column chromatography on silica gel with 50-70% ethyl acetate inhexanes.

Example 79C methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(pyridin-3-yloxy)benzoate

EXAMPLE 79B (367 mg), EXAMPLE 1B (410 mg), and potassium phosphatetribasic (379 mg) were added to 1,2-dimethoxyethane (6 mL). The solutionwas degassed under vacuum and flushed with nitrogen three times.Tris(dibenzylideneacetone)dipalladium(0) (32.7 mg) and2-(di-tert-butylphosphino)biphenyl (42.6 mg) were added and the solutionwas heated to 80° C. for 16 hours. The solution was cooled, filtered,concentrated, and purified by flash column chromatography on silica gelwith 50-70% ethyl acetate in hexanes.

Example 79D4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(pyridin-3-yloxy)benzoicacid

This example was prepared by substituting EXAMPLE 79C for EXAMPLE 1D inEXAMPLE 1E.

Example 79E4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(pyridin-3-yloxy)benzamide

This example was prepared by substituting EXAMPLE 79D for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.72 (broad s,1H), 8.64 (t, 1H), 8.46 (d, 1H), 8.15 (t, 2H), 7.75 (dd, 1H), 7.52-7.44(m, 6H), 7.37 (m, 2H), 7.26-7.10 (m, 4H), 6.79 (dd, 1H), 6.50 (d, 1H),3.87 (dd, 2H), 3.40 (s, 2H), 3.38-3.24 (m, 4H), 3.19 (broad s, 4H), 2.37(broad s, 4H), 1.92 (m, 1H), 1.65 (d, 2H), 1.28 (m, 2H).

Example 804-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(pyridin-3-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 79D for EXAMPLE 1E andEXAMPLE 2A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.34 (s, 1H), 8.27 (dd, 2H), 7.51-7.44 (m, 8H),7.41-7.29 (m, 3H), 7.27-7.19 (m, 2H), 6.78 (dd, 1H), 6.72 (t, 1H), 6.56(d, 2H), 6.44 (d, 1H), 3.86 (dd, 2H), 3.36 (s, 2H), 3.29-3.22 (m, 2H),3.16 (m, 4H), 2.96 (t, 2H), 2.34 (m, 4H), 1.77 (m, 1H), 1.66 (d, 2H),1.21 (m, 2H).

Example 814-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}-2-phenoxybenzamideExample 81A (R)-tert-butyl3-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-hydroxybutanoate

Fmoc-D-Asp(OtBu)-OH (9.0 g) and N,N-diisopropylethylamine (4.6 mL) wereadded to tetrahydrofuran (100 mL) and cooled to −40° C. Isobutylchloroformate (3.1 mL) was added, and the solution was gradually warmedto 0° C. over 30 minutes. The solution was cooled to −20° C., and to itwas carefully added sodium borohydride (1.64 g, 43.6 mmol) and methanol(10 mL). The solution was gradually warmed to room temperature over twohours, diluted with ethyl acetate (200 mL), washed with water (100 mL)and brine (50 mL), dried with anhydrous magnesium sulfate, filtered, andconcentrated to afford crude product of sufficient purity for subsequentuse.

Example 81B (R)-tert-butyl3-(((9H-fluoren-9-yl)methoxy)carbonylamino)-4-(phenylthio)butanoate

Tri-n-butylphosphine (90 μL) and 1,1′-(azodicarbonyl)dipiperidine (91mg) were added to tetrahydrofuran (4 mL), treated with EXAMPLE 81A (90mg) and thiophenol (21 mg), and stirred at room temperature for 18hours. The solution was concentrated and purified by flash columnchromatography on silica gel with 50% ethyl acetate in hexanes.

Example 81C (R)-tert-butyl3-(2-nitro-4-sulfamoylphenylamino)-4-(phenylthio)butanoate

EXAMPLE 81B (600 mg), 4-fluoro-3-nitrobenzenesulfonamide (298 mg), andN,N-diisopropylethylamine (3 mL) were added to N,N-dimethylformamide (3mL) and stirred at 60° C. for 12 hours. The reaction mixture was dilutedwith ethyl acetate (100 mL), washed with water (45 mL) and brine (10mL), dried with anhydrous magnesium sulfate, filtered, and concentrated.The residue was purified by flash column chromatography on silica gelwith 30% ethyl acetate in dichloromethane.

Example 81D(R)-3-(2-nitro-4-sulfamoylphenylamino)-4-(phenylthio)butanoic acid

EXAMPLE 81C (468 mg) and 4 M HCl in 1,4-dioxane (10 mL) were stirred at50° C. for 5 hours. The solution was concentrated to give the crudeproduct of sufficient purity for subsequent use.

Example 81E(R)—N,N-dimethyl-3-(2-nitro-4-sulfamoylphenylamino)-4-(phenylthio)butanamide

This example was prepared by substituting EXAMPLE 81D for EXAMPLE 1E anddimethylamine (2M in tetrahydrofuran) for EXAMPLE 1F in EXAMPLE 1G.

Example 81F(R)-4-(4-(dimethylamino)-1-(phenylthio)butan-2-ylamino)-3-nitrobenzenesulfonamide

To EXAMPLE 81E (4.06 g) was added borane (1 M in tetrahydrofuran, 20.0mL). The solution was stirred at room temperature for 16 hours. Thereaction was quenched slowly with methanol (5.0 mL) and concentratedaqueous HCl (2.0 mL) was added. The solution was stirred at 80° C. forthree hours, cooled to room temperature, carefully basified with 4 Msodium carbonate, diluted with ethyl acetate (150 mL), washed with water(50 mL) and brine (10 mL), dried with anhydrous magnesium sulfate, andfiltered. The solution was concentrated and purified by flash columnchromatography on silica gel with 20% methanol in dichloromethane.

Example 81G4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrophenyl]sulfonyl}-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 81F for EXAMPLE 1F inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.33 (d, 1H), 8.28(d, 1H), 7.61 (dd, 2H), 7.50-7.43 (m, 4H), 7.37-7.14 (m, 11H), 6.90 (t,1H), 6.84 (d, 1H), 6.71 (d, 2H), 6.70 (dd, 1H), 6.32 (d, 1H), 4.06 (m,1H), 3.36 (s, 2H), 3.33-3.30 (m, 2H), 3.08 (t, 4H), 2.86 (m, 2H), 2.53(s, 6H), 2.35 (t, 4H), 2.04 (m, 2H).

Example 824-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(pyridin-4-yloxy)benzamideExample 82A methyl 4-bromo-2-(pyridin-4-yloxy)benzoate

EXAMPLE 79A (800 mg), pyridine-4-ol (359 mg), and potassium carbonate(617 mg) were added to N,N-dimethylacetamide (20 mL) and the mixture washeated to 125° C. for 16 hours. The solution was concentrated on vacuumat 48° C. and purified by flash column chromatography on silica gel with20% methanol in dichloromethane.

Example 82B methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(pyridin-4-yloxy)benzoate

This example was prepared by substituting EXAMPLE 82A for EXAMPLE 79B inEXAMPLE 79C.

Example 82C4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(pyridin-4-yloxy)benzoicacid

This example was prepared by substituting EXAMPLE 82B for EXAMPLE 1D inEXAMPLE 1E.

Example 82D4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(pyridin-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 82C for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.40 (t, 1H), 8.37(d, 1H), 7.76 (dd, 1H), 7.65 (d, 1H), 7.54-7.48 (m, 1H), 7.47 (s, 3H),7.42-7.35 (m, 5H), 7.27-7.23 (m, 1H), 7.06 (dd, 1H), 6.92 (dd, 1H), 6.88(d, 1H), 5.91 (d, 2H), 3.85 (dd, 2H), 3.39 (s, 2H), 3.34-3.25 (m, 4H),3.19 (broad, s, 4H), 2.39 (broad s, 4H), 1.92 (m, 1H), 1.65 (d, 2H),1.27 (m, 2H).

Example 834-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(pyridin-3-yloxy)benzamide

This example was prepared by substituting EXAMPLE 79D for EXAMPLE 1E andEXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.73 (t, 1H), 8.43 (d, 1H), 8.12 (t, 2H), 7.73(dd, 1H), 7.55 (d, 1H), 7.51-7.44 (m, 4H), 7.37 (m, 2H), 7.25-7.17 (m,3H), 7.07 (d, 2H), 6.78 (dd, 1H), 6.47 (d, 1H), 3.65 (t, 4H), 3.47 (q,2H), 3.38 (s, 2H), 3.28 (m, 2H), 3.17 (br s, 4H), 2.57 (br s, 4H), 2.36(br s, 4H), 1.84 (m, 2H).

Example 844-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-(pyridin-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 82C for EXAMPLE 1E andEXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.55 (t, 1H), 8.37 (d, 1H), 7.77 (dd, 1H), 7.65(d, 1H), 7.54-7.43 (m, 5H), 7.42-7.32 (m, 4H), 7.26-7.22 (m, 1H), 7.01(d, 1H), 6.91 (dd, 1H), 6.66 (d, 1H), 5.90 (d, 2H), 3.60 (t, 4H), 3.43(q, 2H), 3.39 (s, 2H), 3.18 (br s, 4H), 2.38 (m, 10H), 1.80 (t, 2H).

Example 854-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[2-(4-methylpiperazin-1-yl)ethyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamideExample 85A4-(2-(4-methylpiperazin-1-yl)ethylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting2-(4-methylpiperazin-1-yl)ethanamine for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 85B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[2-(4-methylpiperazin-1-yl)ethyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 85A for EXAMPLE 1F inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.61 (t, 1H), 8.40(d, 1H), 7.72 (dd, 1H), 7.57 (d, 1H), 7.51-7.44 (m, 5H), 7.36 (m, 2H),7.26-7.15 (m, 3H), 6.95 (t, 2H), 6.75 (dd, 2H), 6.71 (dd, 1H), 6.34 (d,1H), 3.45 (q, 2H), 3.36 (s, 2H), 3.34 (m, 2H), 3.10 (t, 4H), 2.79 (broads, 4H), 2.68 (t, 2H), 2.60 (broad s, 2H), 2.49 (s, 3H), 2.35 (t, 4H).

Example 864-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(4-methylpiperazin-1-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamideExample 86A4-(3-(4-methylpiperazin-1-yl)propylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting3-(4-methylpiperazin-1-yl)propan-1-amine for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 86B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(4-methylpiperazin-1-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 86A for EXAMPLE 1F inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.57 (t, 1H), 8.38(d, 1H), 7.71 (dd, 1H), 7.59 (d, 1H), 7.50-7.44 (m, 5H), 7.36 (m, 2H),7.27-7.15 (m, 3H), 6.98 (d, 2H), 6.91 (t, 1H), 6.73 (dd, 2H), 6.70 (dd,2H), 6.33 (d, 1H), 3.43 (q, 2H), 3.36 (s, 2H), 3.34 (m, 2H), 3.09 (t,4H), 2.82 (broad s, 4H), 2.56 (broad s, 2H), 2.49 (s, 3H), 2.35 (t, 4H),1.79 (t, 2H).

Example 874-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[[3-(dimethylamino)propyl](methyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamideExample 87A4-((3-(dimethylamino)propyl)(methyl)amino)-3-nitrobenzenesulfonamide

This example was prepared by substitutingN¹,N¹,N³-trimethylpropane-1,3-diamine for3-(pyrrolidin-1-yl)propan-1-amine in EXAMPLE 68F.

Example 87B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[[3-(dimethylamino)propyl](methyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 87A for EXAMPLE 1F inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.01 (d, 1H), 7.68(dd, 1H), 7.63 (d, 1H), 7.51-7.44 (m, 5H), 7.36 (m, 2H), 7.26-7.13 (m,3H), 6.93 (t, 1H), 6.83 (m, 1H), 6.74 (dd, 2H), 6.69 (dd, 1H), 6.32 (d,1H), 3.46 (q, 2H), 3.36 (s, 2H), 3.08 (t, 4H), 2.83 (t, 2H), 2.77 (s,3H), 2.60 (s, 6H), 2.36 (t, 4H), 1.86 (m, 2H).

Example 884-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamideExample 88A4-((1-methylpiperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting(1-methylpiperidin-4-yl)methanamine for3-(pyrrolidin-1-yl)propan-1-amine in EXAMPLE 68F.

Example 88B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 88A for EXAMPLE 1F inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.44 (t, 1H), 8.35(d, 1H), 7.79 (dd, 1H), 7.62 (d, 1H), 7.51-7.45 (m, 5H), 7.36 (m, 2H),7.25-7.14 (m, 3H), 6.99 (d, 1H), 6.89 (t, 1H), 6.71 (d, 2H), 6.68 (dd,1H), 6.31 (d, 1H), 3.36 (s, 2H), 3.34 (m, 4H), 3.07 (t, 4H), 2.73 (m,2H), 2.62 (s, 3H), 2.36 (t, 4H), 1.90-1.82 (m, 3H), 1.47-1.31 (m, 2H).

Example 894-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 21A for EXAMPLE 1F inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.38 (t, 1H), 8.09(d, 1H), 7.73 (m, 1H), 7.59 (d, 1H), 7.52-7.44 (m, 5H), 7.36 (m, 2H),7.26-7.22 (m, 1H), 7.17 (t, 1H), 7.05 (d, 1H), 6.90 (t, 1H), 6.83 (m,1H), 6.72 (d, 2H), 6.70 (dd, 1H), 6.33 (d, 1H), 3.36 (q, 2H), 3.36 (s,2H), 3.24-3.12 (m, 2H), 3.09 (t, 4H), 2.80 (m, 1H), 2.59 (s, 3H), 2.36(t, 4H), 2.08 (m, 2H), 1.77 (m, 2H).

Example 904-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-cyano-4-{[3-(dimethylamino)propyl]amino}phenyl)sulfonyl]-2-phenoxybenzamideExample 90A 3-cyano-4-fluorobenzenesulfonamide

Concentrated ammonium hydroxide (28% solution in water, 3.17 mL) wascooled to 0° C. and 3-cyano-4-fluorobenzene-1-sulfonyl chloride (1.00 g)was added. The solution was mixed at 0° C. for four minutes. 4M HCl (10mL) was added slowly and the solution was extracted with ethyl acetate.The extract was dried on brine and anhydrous sodium sulfate and thesolvent removed under vacuum.

Example 90B 3-cyano-4-(3-(dimethylamino)propylamino)benzenesulfonamide

This example was prepared by substituting EXAMPLE 90A for4-chloro-3-nitrobenzenesulfonamide and N¹,N¹-dimethylpropane-1,3-diaminefor 3-(pyrrolidin-1-yl)propan-1-amine in EXAMPLE 68F.

Example 90C4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-cyano-4-{[3-(dimethylamino)propyl]amino}phenyl)sulfonyl]-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 90B for EXAMPLE 1F inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 7.67 (s, 1H), 7.66(dd, 1H), 7.59 (d, 1H), 7.51-7.44 (m, 5H), 7.36 (m, 2H), 7.28-7.20 (m,3H), 6.98 (t, 2H), 6.77 (dd, 2H), 6.70 (d, 2H), 6.33 (d, 1H), 3.36 (s,2H), 3.27 (q, 2H), 3.09 (t, 4H), 2.82 (t, 2H), 2.54 (s, 6H), 2.35 (t,4H), 1.82 (m, 2H).

Example 914-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 68F for EXAMPLE 1F inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.49 (t, 1H), 8.37(d, 1H), 7.72 (dd, 1H), 7.62 (d, 1H), 7.50-7.43 (m, 5H), 7.35 (m, 2H),7.26-7.14 (m, 3H), 6.97 (d, 1H), 6.90 (t, 1H), 6.72 (d, 2H), 6.69 (dd,1H), 6.31 (d, 1H), 3.47 (q, 2H), 3.36 (s, 2H), 3.20 (m, 2H), 3.07 (broads, 8H), 2.35 (broad s, 4H), 1.95-1.83 (m, 6H).

Example 924-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-{[3-(dimethylamino)propyl]amino}-3-(trifluoromethyl)phenyl]sulfonyl}-2-phenoxybenzamideExample 92A 4-fluoro-3-(trifluoromethyl)benzenesulfonamide

This example was prepared by substituting4-fluoro-3-(trifluoromethyl)benzene-1-sulfonyl chloride for3-cyano-4-fluorobenzene-1-sulfonyl chloride in EXAMPLE 90A.

Example 92B4-(3-(dimethylamino)propylamino)-3-(trifluoromethyl)benzenesulfonamide

This example was prepared by substituting EXAMPLE 92A for4-fluoro-3-nitrobenzenesulfonamide and N¹,N¹-dimethylpropane-1,3-diaminefor tetrahydropyran-4-yl)methylamine in EXAMPLE 1F

Example 92C4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-{[3-(dimethylamino)propyl]amino}-3-(trifluoromethyl)phenyl]sulfonyl}-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 92B for EXAMPLE 1F inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 7.77 (s, 1H), 7.68(dd, 1H), 7.57 (d, 1H), 7.51-7.45 (m, 5H), 7.36 (m, 2H), 7.29-7.21 (m,3H), 6.99 (t, 1H), 6.82-6.68 (m, 5H), 6.32 (d, 1H), 3.36 (s, 2H), 3.28(q, 2H), 3.09 (t, 4H), 2.73 (m, 2H), 2.48 (s, 6H), 2.35 (t, 4H), 1.79(m, 2H).

Example 934-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-({3-[isopropyl(methyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-phenoxybenzamideExample 93A tert-butylmethyl(3-(2-nitro-4-sulfamoylphenylamino)propyl)carbamate

This example was prepared by substituting tert-butyl3-aminopropyl(methyl)carbamate for 3-(pyrrolidin-1-yl)propan-1-amine inEXAMPLE 68F.

Example 93B tert-butyl3-(4-(N-(4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoyl)sulfamoyl)-2-nitrophenylamino)propyl(methyl)carbamate

This example was prepared by substituting EXAMPLE 93A for EXAMPLE 1F inEXAMPLE 1G.

Example 93C4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-N-(4-(3-(methylamino)propylamino)-3-nitrophenylsulfonyl)-2-phenoxybenzamide

EXAMPLE 93B (112 mg) and triethylsilane (0.082 mL) were added todichloromethane (2 mL). Trifluoroacetic acid (0.198 mL) was added, thesolution stirred at room temperature for one hour, and the solventremoved under vacuum.

Example 93D4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-{[4-({3-[isopropyl(methyl)amino]propyl}amino)-3-nitrophenyl]sulfonyl}-2-phenoxybenzamide

EXAMPLE 93C (128 mg), acetone (0.014 mL), and sodium cyanoborohydrideresin (2.15 mmol/g, 66 mg) were added to tetrahydrofuran (0.9 mL) andacetic acid (0.3 mL), and the solution was stirred at room temperaturefor 16 hours. More acetone (0.014 mL), and sodium cyanoborohydride resin(66 mg) were added, and the solution was stirred for 24 hours. Thesolution was purified by flash column chromatography on silica gel with1% acetic acid and 10% methanol in dichloromethane. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.93 (broad s, 3H), 8.53 (broad s, 1H), 8.40(d, 1H), 7.75 (dd, 1H), 7.60 (d, 1H), 7.51-7.45 (m, 5H), 7.36 (m, 2H),7.25-7.16 (m, 3H), 7.02 (d, 1H), 6.92 (t, 1H), 6.74 (d, 2H), 6.70 (dd,1H), 6.32 (d, 1H), 3.47 (m, 4H), 3.36 (s, 2H), 3.09 (t, 4H), 3.01 (broads, 2H), 2.58 (s, 3H), 2.35 (t, 4H), 1.94 (m, 1H), 1.18-1.14 (m, 6H).

Example 944-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[3-(dimethylamino)propoxy]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamideExample 94A 4-(3-(dimethylamino)propoxy)-3-nitrobenzenesulfonamide

Triphenylphosphine (1.398 g) was added to tetrahydrofuran (20 mL) andcooled to 0° C. Diethylazodicarboxylate (40% solution, 2.428 mL) wasadded, and the solution was stirred for at 0° C. for 15 minutes.4-Hydroxy-3-nitrobenzenesulfonamide (1.163 g) and3-(dimethylamine)propan-1-ol (0.567 mL) were added, and the solution wasallowed to warm to room temperature and stir for 16 hours. Solvent wasremoved under vacuum and the material recrystallized using 20% methanol(dichloromethane). The recrystallized solid was washed withdichloromethane, dissolved in methanol/dichloromethane, treated withtriethylamine (0.13 mL, 0.924 mmol), and purified by flash columnchromatography on silica gel with 10-20% methanol in dichloromethane.

Example 94B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[3-(dimethylamino)propoxy]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 94A for EXAMPLE 1F inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.06 (d, 1H), 7.84(dd, 1H), 7.65 (d, 1H), 7.52-7.45 (m, 5H), 7.36 (m, 2H), 7.26-7.22 (m,2H), 7.18 (td, 2H), 6.89 (t, 1H), 6.69 (d, 1H), 6.68 (d, 2H), 6.32 (d,1H), 4.25 (t, 2H), 3.36 (s, 2H), 3.13 (t, 2H), 3.08 (t, 4H), 2.75 (s,6H), 2.36 (t, 4H), 2.11 (m, 2H).

Example 954-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(4-methylpiperazin-1-yl)ethyl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 85A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.10 (s, 1H), 8.67 (t, 1H), 8.53 (d, 1H), 7.78(dd, 1H), 7.52 (d, 1H), 7.39-7.31 (m, 4H), 7.08-7.02 (m, 3H), 6.94 (d,1H), 6.80 (dd, 1H), 6.61 (dd, 1H), 6.36 (t, 1H), 6.14 (d, 1H), 3.42 (q,2H), 2.99 (t, 4H), 2.71 (s, 2H), 2.70-2.48 (m, 10H), 2.39 (s, 3H), 2.16(m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 964-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[3-(4-methylpiperazin-1-yl)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 86A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.09 (s, 1H), 8.62 (t, 1H), 8.51 (d, 1H), 7.76(dd, 1H), 7.53 (d, 1H), 7.38-7.31 (m, 4H), 7.05 (s, 1H), 7.02 (d, 2H),6.96 (d, 1H), 6.79 (dd, 1H), 6.60 (dd, 1H), 6.35 (t, 1H), 6.14 (d, 1H),3.40 (q, 2H), 2.98 (t, 4H), 2.71 (s, 2H), 2.67 (broad s, 4H), 2.55-2.40(m, 6H), 2.39 (s, 3H), 2.16 (m, 6H), 1.95 (s, 2H), 1.77 (m, 2H), 1.38(t, 2H), 0.92 (s, 6H).

Example 974-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 68F for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.06 (s, 1H), 8.58 (t, 1H), 8.49 (d, 1H), 7.77(dd, 1H), 7.54 (d, 1H), 7.36-7.31 (m, 4H), 7.06-7.01 (m, 3H), 6.95 (d,1H), 6.76 (dd, 1H), 6.57 (dd, 1H), 6.35 (t, 1H), 6.14 (d, 1H), 3.44 (q,2H), 2.97 (broad s, 10H), 2.71 (s, 2H), 2.16 (m, 6H), 1.95 (s, 2H),1.90-1.80 (m, 6H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 984-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.08 (s, 1H), 8.51 (d, 1H), 8.13 (d, 1H), 7.78(dd, 1H), 7.52 (d, 1H), 7.37-7.31 (m, 4H), 7.06-7.00 (m, 4H), 6.79 (dd,1H), 6.59 (dd, 1H), 6.35 (t, 1H), 6.14 (d, 1H), 3.73 (m, 1H), 3.05-2.95(m, 6H), 2.71 (s, 2H), 2.60 (m, 2H), 2.48 (s, 3H), 2.16 (m, 6H), 2.01(m, 2H), 1.95 (s, 2H), 1.70 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 994-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[3-(4-methylpiperazin-1-yl)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 1E andEXAMPLE 86A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.16 (s, 1H), 8.59 (t, 1H), 8.45 (d, 1H), 7.72(dd, 1H), 7.55 (d, 1H), 7.34 (d, 2H), 7.23 (t, 1H), 7.12 (d, 1H), 7.02(d, 2H), 6.95 (d, 1H), 6.94 (t, 1H), 6.64 (dd, 1H), 6.35 (d, 1H), 6.23(m, 2H), 3.41 (q, 2H), 2.98 (t, 4H), 2.71 (broad s, 6H), 2.52-2.42 (m,6H), 2.41 (s, 3H), 2.15 (m, 6H), 1.95 (s, 2H), 1.77 (m, 2H), 1.38 (t,2H), 0.92 (s, 6H).

Example 1004-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[3-(dimethylamino)propoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 94A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.03 (s, 1H), 8.23 (d, 1H), 7.91 (dd, 1H), 7.56(d, 1H), 7.36-7.29 (m, 4H), 7.19 (d, 1H), 7.05 (d, 2H), 6.97 (s, 1H),6.73 (dd, 1H), 6.57 (dd, 1H), 6.33 (t, 1H), 6.15 (d, 1H), 4.23 (t, 2H),3.04 (m, 2H), 2.96 (t, 4H), 2.72 (s, 2H), 2.67 (s, 6H), 2.22-2.02 (m,8H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 1014-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(4-methylpiperazin-1-yl)ethyl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 1E andEXAMPLE 85A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.18 (s, 1H), 8.64 (t, 1H), 8.47 (d, 1H), 7.73(dd, 2H), 7.56 (d, 1H), 7.34 (d, 2H), 7.24 (t, 1H), 7.04 (d, 2H), 6.96(d, 1H), 6.94 (d, 1H), 6.65 (dd, 1H), 6.37 (d, 1H), 6.23 (m, 2H), 3.43(q, 2H), 2.99 (t, 4H), 2.71 (s, 2H), 2.65 (m, 6H), 2.56 (m, 4H), 2.42(s, 3H), 2.15 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 1024-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 1E andEXAMPLE 68F for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.14 (s, 1H), 8.54 (t, 1H), 8.44 (d, 1H), 7.76(dd, 1H), 7.59 (d, 1H), 7.34 (d, 2H), 7.22 (t, 1H), 7.10 (d, 1H), 7.05(d, 2H), 6.98-6.89 (m, 2H), 6.62 (dd, 1H), 6.33 (d, 1H), 6.23 (t, 1H),6.21 (d, 1H), 3.44 (q, 2H), 3.10-2.91 (m, 10H), 2.71 (s, 2H), 2.16 (m,6H), 1.95 (s, 2H), 1.92-1.79 (m, 6H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 1034-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 1E andEXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.14 (s, 1H), 8.44 (d, 1H), 8.11 (d, 1H), 7.75(dd, 1H), 7.56 (d, 1H), 7.34 (d, 2H), 7.23 (t, 1H), 7.11 (d, 1H), 7.04(d, 2H), 7.03 (d, 1H), 6.93 (t, 1H), 6.64 (dd, 1H), 6.34 (d, 1H), 6.22(m, 2H), 3.73 (m, 1H), 3.08-2.93 (m, 6H), 2.71 (s, 2H), 2.70-2.56 (m,2H), 2.48 (s, 3H), 2.16 (m, 6H), 2.02 (m, 2H), 1.95 (s, 2H), 1.70 (m,2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 1044-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 88A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 10.99 (s, 1H), 8.39 (d, 1H), 8.32 (t, 1H), 7.65(dd, 1H), 7.54 (d, 1H), 7.34 (d, 2H), 7.30-7.26 (m, 2H), 7.05 (d, 2H),6.92 (d, 1H), 6.81 (d, 1H), 6.70 (dd, 1H), 6.53 (dd, 1H), 6.30 (t, 1H),6.15 (d, 1H), 3.28-3.19 (m, 2H), 2.93 (t, 4H), 2.83 (m, 2H), 2.71 (s,2H), 2.68-2.50 (m, 2H), 2.54 (s, 3H), 2.24-2.10 (m, 6H), 1.95 (broad s,2H), 1.68 (d, 2H), 1.59 (m, 1H), 1.38 (t, 2H), 1.32-1.17 (m, 2H), 0.92(s, 6H).

Example 1054-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 1E andEXAMPLE 88A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.11 (s, 1H), 8.44 (t, 1H), 8.41 (d, 1H), 7.74(dd, 1H), 7.59 (d, 1H), 7.34 (d, 2H), 7.21 (t, 1H), 7.11-7.02 (m, 3H),6.98-6.90 (m, 2H), 6.61 (dd, 1H), 6.31 (d, 1H), 6.23 (t, 1H), 6.20 (d,1H), 3.20 (m, 2H), 2.95 (t, 4H), 2.71 (s, 2H), 2.62-2.49 (m, 4H), 2.55(s, 3H), 2.16 (m, 6H), 1.95 (s, 2H), 1.86-1.78 (m, 3H), 1.42-1.31 (m,4H), 0.92 (s, 6H).

Example 1064-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[3-(dimethylamino)propoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 1E andEXAMPLE 94A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.10 (s, 1H), 8.16 (d, 1H), 7.90 (dd, 1H), 7.61(d, 1H), 7.35 (d, 2H), 7.24-7.19 (m, 2H), 7.10-7.01 (m, 3H), 6.91 (t,1H), 6.60 (dd, 1H), 6.28 (d, 1H), 6.23 (t, 1H), 6.20 (d, 1H), 4.23 (t,2H), 3.03 (t, 2H), 2.95 (t, 4H), 2.72 (s, 2H), 2.67 (s, 6H), 2.17 (m,6H), 2.07 (m, 2H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 1074-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(4-methylpiperazin-1-yl)-3-nitrophenyl]sulfonyl}benzamideExample 107A 4-(4-methylpiperazin-1-yl)-3-nitrobenzenesulfonamide

This example was prepared by substituting 1-methylpiperazine for3-(pyrrolidin-1-yl)propan-1-amine in EXAMPLE 68F.

Example 107B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(4-methylpiperazin-1-yl)-3-nitrophenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 107A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.21 (s, 1H), 8.18 (d, 1H), 7.77 (dd, 1H), 7.57(d, 1H), 7.34 (d, 2H), 7.26 (t, 1H), 7.22 (d, 1H), 7.16 (d, 1H),7.07-7.02 (m, 2H), 6.96 (t, 1H), 6.87 (dd, 1H), 6.39 (d, 1H), 6.25 (m,2H), 3.16 (m, 4H), 3.01 (t, 4H), 2.73 (s, 2H), 2.66 (broad s, 4H), 2.39(s, 3H), 2.18 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 1084-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamideExample 108A3-nitro-4-(1-(2,2,2-trifluoroethyl)piperidin-4-ylamino)benzenesulfonamide

4-chloro-3-nitrobenzenesulfonamide (1.300 g),1-(2,2,2-trifluoroethyl)piperidin-4-amine hydrochloride (1.201 g), andtriethylamine (2.30 mL) were added to 1,4-dioxane (50 mL) and water (5mL) and heated at 90° C. for 16 hours. The solution was concentrated onvacuum and purified by flash column chromatography on silica gel withethyl acetate increasing to 5% methanol in ethyl acetate.

Example 108B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide

This EXAMPLE was prepared by substituting EXAMPLE 55B for EXAMPLE 1E andEXAMPLE 108A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.24 (s, 1H), 8.50 (d, 1H), 8.25 (d, 1H), 7.71(dd, 1H), 7.52 (d, 1H), 7.34 (d, 2H), 7.27 (t, 1H), 7.17 (d, 1H), 7.11(d, 1H), 7.04 (d, 2H), 6.97 (t, 1H), 6.71 (dd, 1H), 6.43 (d, 1H), 6.28(d, 1H), 6.24 (t, 1H), 3.68 (m, 1H), 3.23 (q, 2H), 3.06 (broad s, 4H),2.95-2.87 (m, 2H), 2.78-2.71 (m, 2H), 2.58 (t, 2H), 2.25-2.11 (m, 6H),1.98-1.85 (m, 4H), 1.64 (m, 2H), 1.39 (t, 2H), 0.92 (s, 6H).

Example 1094-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(dimethylamino)-1-methylpiperidin-4-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamideExample 109A4-((4-(dimethylamino)-1-methylpiperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting4-(aminomethyl)-N,N,1-trimethylpiperidin-4-amine for1-(2,2,2-trifluoroethyl)piperidin-4-amine hydrochloride in EXAMPLE 108A.

Example 109B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(dimethylamino)-1-methylpiperidin-4-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 109A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.06 (s, 1H), 8.56 (broad s, 1H), 8.50 (d, 1H),7.81 (dd, 1H), 7.54 (d, 1H), 7.36-7.31 (m, 4H), 7.08-7.02 (m, 4H), 6.77(dd, 1H), 6.57 (dd, 1H), 6.34 (t, 1H), 6.13 (d, 1H), 3.50 (d, 2H), 3.04(m, 2H), 2.96 (t, 4H), 2.87 (m, 2H), 2.71 (s, 2H), 2.58 (s, 3H), 2.28(s, 6H), 2.16 (m, 6H), 1.98 (m, 2H), 1.95 (s, 2H), 1.65-1.54 (m, 2H),1.38 (t, 2H), 0.94 (s, 6H).

Example 1104-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(2,3-dihydro-1,4-benzodioxin-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 110A methyl4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-5-yloxy)benzoate

This example was prepared by substituting EXAMPLE 34A for EXAMPLE 18Eand 2,3-dihydrobenzo[b][1,4]dioxin-5-ol for phenol in EXAMPLE 18F.

Example 110B4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydrobenzo[b][1,4]dioxin-5-yloxy)benzoicacid

This example was prepared by substituting EXAMPLE 110A for EXAMPLE 1D inEXAMPLE 1E.

Example 110C4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(2,3-dihydro-1,4-benzodioxin-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 110B for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 11.40 (s, 1H),8.65 (t, 1H), 8.55 (d, 1H), 7.83 (dd, 1H), 7.46 (m, 6H), 7.36 (m, 2H),7.23 (m, 2H), 6.77 (d, 1H), 6.70 (dd, 1H), 6.42 (m, 2H), 6.27 (d, 1H),4.20 (s, 4H), 3.85 (dd, 2H), 3.37 (m, 4H), 3.25 (m, 2H), 3.13 (m, 4H),2.35 (m, 4H), 1.90 (m, 1H), 1.62 (dd, 2H), 1.27 (m, 2H).

Example 1115-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-1,1′-biphenyl-2-carboxamideExample 111A methyl5-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)biphenyl-2-carboxylate

EXAMPLE 34A (100 mg, 0.2 mmol) in tetrahydrofuran (1.5 mL) was treatedwith phenylboronic acid (36.6 mg, 0.3 mmol),tris(dibenzylideneacetone)dipalladium(0) (9.2 mg, 0.01 mmol),tri-tert-butylphosphonium tetrafluoroborate (5.8 mg, 0.02 mmol) andcesium fluoride (91 mg, 0.6 mmol), flushed with nitrogen and stirredovernight at ambient temperature. The reaction mixture was diluted withethyl acetate, washed with water and brine, dried (MgSO₄), filtered andconcentrated. The concentrate was purified by column chromatography onsilica gel eluting with a gradient of 0 to 3% methanol in CH₂Cl₂ to givethe product.

Example 111B5-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)biphenyl-2-carboxylicacid

This example was prepared by substituting EXAMPLE 111A for EXAMPLE 1D inEXAMPLE 1E.

Example 111C5-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-1,1′-biphenyl-2-carboxamide

This example was prepared by substituting EXAMPLE 111B for EXAMPLE 27Gin EXAMPLE 27H. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ ppm 12.09 (s,1H), 8.72 (t, 1H), 8.46 (d, 1H), 7.79 (m, 2H), 7.52 (m, 4H), 7.35 (dd,5H), 7.16 (m, 1H), 7.04 (m, 4H), 6.91 (dd, 1H), 6.78 (m, 1H), 4.39 (m,1H), 3.88 (m, 3H), 3.42 (m, 4H), 3.27 (m, 4H), 2.96 (m, 4H), 1.95 (m,1H), 1.67 (m, 2H), 1.31 (m, 2H).

Example 1125-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-1,1′-biphenyl-2-carboxamide

This example was prepared by substituting EXAMPLE 111B for EXAMPLE 27Gand EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 12.09 (s, 1H), 8.74 (t, 1H), 8.47 (d, 1H),7.83 (dd, 1H), 7.70 (m, 1H), 7.40 (m, 8H), 7.27 (m, 1H), 7.20 (m, 1H),7.07 (m, 4H), 6.91 (dd, 1H), 6.77 (m, 1H), 4.39 (m, 1H), 3.87 (m, 1H),3.55 (m, 4H), 3.26 (m, 2H), 3.16 (m, 4H), 3.03 (m, 2H), 2.80 (m, 6H),1.98 (m, 2H).

Example 1134-[4-({4′-chloro-4-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamideExample 113A methyl 2-phenoxy-4-(piperazin-1-yl)benzoate

This example was made by substituting piperazine for EXAMPLE 1B inEXAMPLE 1D.

Example 113B methyl4-(4-(2-bromo-5-hydroxybenzyl)piperazin-1-yl)-2-phenoxybenzoate

This example was made by substituting 2-bromo-5-hydroxybenzaldehyde for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 113A for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 113C methyl4-(4-(2-bromo-5-(2-(dimethylamino)ethoxy)benzyl)piperazin-1-yl)-2-phenoxybenzoate

A mixture of EXAMPLE 113B (170 mg), 2-chloro-N,N-dimethylethanaminehydrochloride salt (80 mg) and cesium carbonate (278 mg) was suspendedin anhydrous N,N-dimethylformamide (3 mL). The reaction mixture washeated at 50° C. overnight. The reaction mixture was cooled to roomtemperature and diluted with ethyl acetate. The organic phase was washedwith water and brine, and dried over anhydrous Na₂SO₄. The solvent wasremoved under vacuum to afford an oily residue which was used in thenext step without further purification.

Example 113D methyl4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoate

This example was made by substituting EXAMPLE 113C for EXAMPLE 68C and4-chlorophenylboronic acid for 4-methoxyphenylboronic acid in EXAMPLE68D.

Example 113E4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoicacid

This example was made by substituting EXAMPLE 113D for EXAMPLE 1D inEXAMPLE 1E.

Example 113F4-[4-({4′-chloro-4-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide

This example was made by substituting EXAMPLE 113E for EXAMPLE 1E inEXAMPLE 27H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.69 (br s, 1H),9.87 (br s, 1H), 8.63 (t, 1H), 8.46 (d, 1H), 7.75 (dd, 1H), 7.50 (m,3H), 7.34-7.23 (m, 6H), 7.14 (m, 2H), 6.98 (m, 1H), 6.78 (m, 3H), 6.44(d, 1H), 4.37 (t, 2H), 3.86 (m, 2H), 3.60-3.41 (m, 10H), 3.34 (t, 4H),3.28 (m, 2H), 2.89 (s, 6H), 1.91 (m, 1H), 1.62 (m, 2H), 1.28 (m, 2H).

Example 1144-(4-{[4′-chloro-4-(3-piperidin-1-ylpropoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamideExample 114A methyl4-(4-(2-bromo-5-(3-(piperidin-1-yl)propoxy)benzyl)piperazin-1-yl)-2-phenoxybenzoate

This example was made by substituting 1-(3-chloropropyl)piperidinehydrochloride salt for 2-chloro-N,N-dimethylethanamine hydrochloridesalt in EXAMPLE 113C.

Example 114B methyl4-(4-((4′-chloro-4-(3-(piperidin-1-yl)propoxy)biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoate

This example was made by substituting EXAMPLE 114A for EXAMPLE 68C and4-chlorophenylboronic acid for 4-methoxyphenylboronic acid in EXAMPLE68D.

Example 114C4-(4-((4′-chloro-4-(3-(piperidin-1-yl)propoxy)biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoicacid

This example was made by substituting EXAMPLE 114B for EXAMPLE 1D inEXAMPLE 1E.

Example 114D4-(4-{[4′-chloro-4-(3-piperidin-1-ylpropoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide

This example was made by substituting EXAMPLE 114C for EXAMPLE 1E inEXAMPLE 27H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.69 (br s, 1H),9.18 (br s, 1H), 8.63 (t, 1H), 8.46 (d, 1H), 7.75 (dd, 1H), 7.50 (m,3H), 7.33-7.21 (m, 6H), 7.15 (d, 2H), 6.98 (m, 1H), 6.78 (m, 3H), 6.44(d, 1H), 4.11 (t, 2H), 3.87 (dd, 2H), 3.60-3.38 (m, 10H), 3.34 (m, 4H),3.25 (m, 4H), 2.92 (m, 2H), 2.17 (m, 2H), 1.85 (m, 3H), 1.64 (m, 6H),1.29 (m, 2H).

Example 1154-(4-{[4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamideExample 115A methyl4-(4-(2-bromo-5-(2-morpholinoethoxy)benzyl)piperazin-1-yl)-2-phenoxybenzoate

This example was made by substituting 4-(2-chloroethyl)morpholinehydrochloride salt for 2-chloro-N,N-dimethylethanamine hydrochloridesalt in EXAMPLE 113C.

Example 115B methyl4-(4-((4′-chloro-4-(2-morpholinoethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoate

This example was made by substituting EXAMPLE 115A for EXAMPLE 68C and4-chlorophenylboronic acid for 4-methoxyphenylboronic acid in EXAMPLE68D.

Example 115C4-(4-((4′-chloro-4-(2-morpholinoethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoicacid

This example was made by substituting EXAMPLE 115B for EXAMPLE 1D inEXAMPLE 1E.

Example 115D4-(4-{[4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide

This example was made by substituting EXAMPLE 115C for EXAMPLE 1E inEXAMPLE 27H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.66 (br s, 1H),8.63 (t, 1H), 8.46 (d, 1H), 7.75 (dd, 1H), 7.50 (m, 3H), 7.31 (m, 4H),7.23 (m, 2H), 7.15 (m, 2H), 6.98 (m, 1H), 6.78 (m, 3H), 6.44 (d, 1H),4.41 (m, 2H), 3.87 (m, 6H), 3.60-3.38 (m, 12H), 3.36-3.25 (m, 8H), 1.91(m, 1H), 1.64 (m, 2H), 1.29 (m, 2H).

Example 1164-[4-({4′-chloro-4-[3-(dimethylamino)propoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamideExample 116A methyl4-(4-(2-bromo-5-(3-(dimethylamino)propoxy)benzyl)piperazin-1-yl)-2-phenoxybenzoate

This example was made by substituting3-chloro-N,N-dimethylpropan-1-amine hydrochloride salt for2-chloro-N,N-dimethylethanamine hydrochloride salt in EXAMPLE 113C.

Example 116B methyl4-(4-((4′-chloro-4-(3-(dimethylamino)propoxy)biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoate

This example was made by substituting EXAMPLE 116A for EXAMPLE 68C and4-chlorophenylboronic acid for 4-methoxyphenylboronic acid in EXAMPLE68D.

Example 116C4-(4-((4′-chloro-4-(3-(dimethylamino)propoxy)biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoicacid

This example was made by substituting EXAMPLE 116B for EXAMPLE 1D inEXAMPLE 1E.

Example 116D4-[4-({4′-chloro-4-[3-(dimethylamino)propoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide

This example was made by substituting EXAMPLE 116C for EXAMPLE 1E inEXAMPLE 27H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.64 (br s, 1H),9.52 (br s, 1H), 8.63 (t, 1H), 8.47 (d, 1H), 7.75 (dd, 1H), 7.50 (m,3H), 7.34 (m, 2H), 7.23 (m, 4H), 7.14 (d, 1H), 6.98 (m, 2H), 6.78 (m,3H), 6.42 (s, 1H), 4.09 (t, 2H), 3.86 (m, 2H), 3.50-3.36 (m, 8H), 3.28(m, 8H), 2.83 (s, 6H), 2.12 (m, 2H), 1.91 (m, 1H), 1.62 (m, 2H), 1.29(m, 2H).

Example 1174-(4-{[4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was made by substituting EXAMPLE 115C for EXAMPLE 27G andEXAMPLE 163A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.11 (d, 1H), 7.86 (dd, 1H), 7.49 (m, 3H),7.36-7.26 (m, 7H), 7.10 (m, 3H), 6.84 (d, 2H), 6.77 (dd, 1H), 6.41 (s,1H), 4.38 (m, 2H), 3.84 (m, 4H), 3.55 (m, 2H), 3.50-3.30 (m, 10H), 3.28(m, 8H), 3.20 (m, 2H), 1.86 (m, 1H), 1.55 (m, 2H), 1.26 (m, 2H).

Example 1184-(4-{[4′-chloro-4-(3-piperidin-1-ylpropoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was made by substituting EXAMPLE 114C for EXAMPLE 27G andEXAMPLE 163A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.65 (br s, 1H), 9.06 (br s, 1H), 8.11 (d, 1H),7.86 (dd, 1H), 7.49 (m, 3H), 7.36-7.20 (m, 7H), 7.06 (m, 3H), 6.83 (d,2H), 6.76 (dd, 1H), 6.41 (s, 1H), 4.10 (t, 2H), 3.85 (dd, 2H), 3.40-3.05(m, 16H), 2.90 (m, 2H), 2.15 (m, 2H), 1.84 (m, 3H), 1.60 (m, 6H), 1.41(m, 2H), 1.26 (m, 2H).

Example 1194-[4-({4′-chloro-4-[3-(dimethylamino)propoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was made by substituting EXAMPLE 116C for EXAMPLE 27G andEXAMPLE 163A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.11 (d, 1H), 7.86 (dd, 1H), 7.49 (m, 3H),7.36-7.26 (m, 7H), 7.06 (m, 3H), 6.84 (d, 2H), 6.76 (dd, 1H), 6.41 (d,1H), 4.09 (t, 2H), 3.84 (dd, 2H), 3.50-3.24 (m, 14H), 3.10 (m, 2H), 2.83(s, 6H), 2.12 (m, 2H), 1.86 (m, 1H), 1.55 (m, 2H), 1.26 (m, 2H).

Example 1204-[4-({4′-chloro-4-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was made by substituting EXAMPLE 113E for EXAMPLE 27G andEXAMPLE 163A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.75 (br s, 1H), 9.90 (br s, 1H), 8.10 (d, 1H),7.85 (dd, 1H), 7.49 (m, 3H), 7.38-7.25 (m, 7H), 7.11 (d, 2H), 7.03 (m,1H), 6.82 (d, 2H), 6.77 (dd, 1H), 6.44 (s, 1H), 4.37 (t, 2H), 3.85 (m,6H), 3.55 (m, 2H), 3.29 (m, 8H), 3.10 (m, 2H), 2.89 (s, 6H), 1.86 (m,1H), 1.55 (m, 2H), 1.24 (m, 2H).

Example 1214-[4-({4′-chloro-4-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide

This example was made by substituting EXAMPLE 113E for EXAMPLE 27G andEXAMPLE 68F for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.70 (br s, 1H), 9.95 (br s, 1H), 9.73 (br s,1H), 8.69 (t, 1H), 8.49 (d, 1H), 7.79 (dd, 1H), 7.50 (m, 3H), 7.34 (m,2H), 7.23 (m, 3H), 7.16 (d, 1H), 7.09 (m, 1H), 7.00 (m, 1H), 6.82 (d,2H), 6.77 (dd, 1H), 6.42 (s, 1H), 4.37 (m, 2H), 3.70 (m, 6H), 3.54 (m,8H), 3.21 (m, 4H), 3.19 (m, 2H), 2.88 (s, 6H), 1.97 (m, 4H), 1.85 (m,2H).

Example 1224-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamideExample 122A methyl4-(4-(2-bromo-6-hydroxybenzyl)piperazin-1-yl)-2-phenoxybenzoate

This example was made by substituting 2-bromo-6-hydroxybenzaldehyde for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 113A for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 122B methyl4-(4-((4′-chloro-3-hydroxybiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoate

This example was made by substituting EXAMPLE 122A for EXAMPLE 68C and4-chlorophenylboronic acid for 4-methoxyphenylboronic acid in EXAMPLE68D.

Example 122C methyl4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoate

EXAMPLE 122B (100 mg) and 2-chloro-N,N-dimethylethanamine hydrochloridesalt (30 mg) was dissolved in mixed solvent of dichloromethane (1.5 mL)and 50% sodium hydroxide aqueous solution (0.5 mL), followed by additionof tetrabutylammonium iodide (15 mg). The reaction mixture was stirredat room temperature overnight. The reaction mixture was diluted withethyl acetate, and washed with water and brine. The organic phase wasdried over Na₂SO₄ and concentrated. Flash column purification wasperformed with 0-5% methanol/dichloromethane to afford the product.

Example 122D4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoicacid

This example was made by substituting EXAMPLE 122C for EXAMPLE 1D inEXAMPLE 1E.

Example 122E4-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide

This example was made by substituting EXAMPLE 122D for EXAMPLE 1E inEXAMPLE 27H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 10.20 (br s, 1H),9.46 (br s, 1H), 8.65 (t, 1H), 8.47 (d, 1H), 7.78 (d, 1H), 7.75 (dd,1H), 7.52 (m, 4H), 7.38 (m, 3H), 7.23 (m, 3H), 7.12 (m, 1H), 6.98 (m,2H), 6.78 (d, 2H), 6.76 (dd, 1H), 6.43 (s, 1H), 4.43 (m, 2H), 3.87 (m,2H), 3.62 (m, 4H), 3.35-3.15 (m, 12H), 2.90 (s, 6H), 1.90 (m, 1H), 1.62(m, 2H), 1.27 (m, 2H).

Example 1234-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide

This example was made by substituting EXAMPLE 122C for EXAMPLE 1E andEXAMPLE 68F for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 10.01 (br s, 1H), 9.63 (br s, 1H), 9.32 (br s,1H), 8.69 (t, 1H), 8.49 (d, 1H), 7.80 (dd, 1H), 7.52 (m, 4H), 7.38 (m,2H), 7.25 (m, 3H), 7.15 (d, 1H), 7.01 (m, 1H), 6.95 (m, 1H), 6.81 (d,2H), 6.76 (m, 1H), 6.41 (s, 1H), 4.43 (m, 4H), 3.56-3.51 (m, 8H), 3.20(m, 4H), 3.10 (m, 6H), 2.91 (s, 6H), 1.98 (m, 4H), 1.85 (m, 2H).

Example 1244-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was made by substituting EXAMPLE 122C for EXAMPLE 27G andEXAMPLE 163A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.71 (br s, 1H), 9.89 (br s, 1H), 9.14 (br s,1H), 8.11 (d, 1H), 7.86 (dd, 1H), 7.52 (m, 4H), 7.38 (m, 2H), 7.29 (m,3H), 7.20 (m, 1H), 7.11 (d, 1H), 7.05 (m, 1H), 6.95 (m, 1H), 6.83 (d,2H), 6.76 (dd, 1H), 6.40 (s, 1H), 4.41 (m, 2H), 3.85 (m, 2H), 3.59 (m,4H), 3.44 (m, 2H), 3.28 (m, 8H), 3.06 (m, 2H), 2.91 (s, 6H), 1.84 (m,1H), 1.55 (m, 2H), 1.26 (m, 2H).

Example 1254-[4-({4′-chloro-4-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 125A 4′-chloro-4-hydroxybiphenyl-2-carbaldehyde

This example was made by substituting 2-bromo-5-hydroxybenzaldehyde forEXAMPLE 68C and 4-chlorophenylboronic acid for 4-methoxyphenylboronicacid in EXAMPLE 68D.

Example 125B4′-chloro-4-(2-(dimethylamino)ethoxy)biphenyl-2-carbaldehyde

This example was made by substituting EXAMPLE 125A for EXAMPLE 122B inEXAMPLE 122C.

Example 125C methyl2-(1H-indol-4-yloxy)-4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was made by substituting EXAMPLE 125B for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 125D2-(1H-indol-4-yloxy)-4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was made by substituting EXAMPLE 125C for EXAMPLE 1D inEXAMPLE 1E.

Example 125E4-[4-({4′-chloro-4-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was made by substituting EXAMPLE 125D for EXAMPLE 1E inEXAMPLE 27H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.46 (br s, 1H),11.25 (s, 1H), 9.80 (br s, 1H), 8.60 (t, 1H), 8.48 (d, 1H), 7.65 (dd,1H), 7.55 (d, 1H), 7.46 (d, 2H), 7.28 (m, 5H), 7.15 (d, 1H), 7.10 (m,1H), 7.04 (d, 1H), 6.94 (m, 1H), 6.73 (dd, 1H), 6.36 (m, 2H), 6.26 (m,1H), 4.35 (t, 2H), 3.85 (m, 6H), 3.54 (m, 4H), 3.31 (m, 6H), 3.06 (m,2H), 2.88 (s, 6H), 1.88 (m, 1H), 1.60 (m, 2H), 1.28 (m, 2H).

Example 1264-[4-({4′-chloro-4-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 126A methyl2-(1H-indol-5-yloxy)-4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was made by substituting EXAMPLE 125B for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 150A for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 126B2-(1H-indol-5-yloxy)-4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was made by substituting EXAMPLE 126A for EXAMPLE 1D inEXAMPLE 1E.

Example 126C4-[4-({4′-chloro-4-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was made by substituting EXAMPLE 126B for EXAMPLE 1E inEXAMPLE 27H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.35 (br s, 1H),11.17 (s, 1H), 9.85 (br s, 1H), 8.61 (t, 1H) 8.57 (d, 1H), 7.77 (dd,1H), 7.54 (d, 1H), 7.46 (d, 2H), 7.38 (m, 2H), 7.30 (m, 4H), 7.09 (m,3H), 6.84 (dd, 1H), 6.69 (dd, 1H), 6.36 (m, 1H), 6.26 (m, 1H), 4.35 (t,2H), 3.85 (m, 6H), 3.54 (m, 4H), 3.31 (m, 6H), 3.06 (m, 2H), 2.88 (s,6H), 1.88 (m, 1H), 1.60 (m, 2H), 1.28 (m, 2H).

Example 1274-(4-{[4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 127A 4′-chloro-4-(2-morpholinoethoxy)biphenyl-2-carbaldehyde

This example was made by substituting EXAMPLE 125A for EXAMPLE 122B inand 4-(2-chloroethyl)morpholine hydrochloride salt for2-chloro-N,N-dimethylethanamine hydrochloride salt EXAMPLE 122C.

Example 127B methyl2-(1H-indol-5-yloxy)-4-(4-((4′-chloro-4-(2-morpholinoethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was made by substituting EXAMPLE 127A for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 150A for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 127C2-(1H-indol-5-yloxy)-4-(4-((4′-chloro-4-(2-morpholinoethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was made by substituting EXAMPLE 127B for EXAMPLE 1D inEXAMPLE 1E.

Example 127D4-(4-{[4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was made by substituting EXAMPLE 127C for EXAMPLE 1E inEXAMPLE 27H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.35 (br s, 1H),11.17 (s, 1H), 8.61 (t, 1H), 8.57 (d, 1H), 7.77 (dd, 1H), 7.54 (d, 1H),7.46 (d, 2H), 7.38 (m, 2H), 7.29 (m, 4H), 7.09 (m, 3H), 6.84 (dd, 1H),6.69 (dd, 1H), 6.36 (m, 1H), 6.26 (d, 1H), 4.39 (t, 2H), 3.85 (m, 6H),3.54 (m, 10H), 3.31 (m, 8H), 3.06 (m, 2H), 1.88 (m, 1H), 1.60 (m, 2H),1.27 (m, 2H).

Example 1284-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 128A 4′-chloro-3-hydroxybiphenyl-2-carbaldehyde

This example was made by substituting 2-bromo-6-hydroxybenzaldehyde forEXAMPLE 68C and 4-chlorophenylboronic acid for 4-methoxyphenylboronicacid in EXAMPLE 68D.

Example 128B4′-chloro-3-(2-(dimethylamino)ethoxy)biphenyl-2-carbaldehyde

This example was made by substituting EXAMPLE 128A for EXAMPLE 122B inEXAMPLE 122C.

Example 128C methyl2-(1H-indol-4-yloxy)-4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was made by substituting EXAMPLE 128B for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 128D2-(1H-indol-4-yloxy)-4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was made by substituting EXAMPLE 128C for EXAMPLE 1D inEXAMPLE 1E.

Example 128E4-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was made by substituting EXAMPLE 128D for EXAMPLE 1E inEXAMPLE 27H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.15 (s, 1H),8.47 (t, 1H) 8.45 (d, 1H), 7.68 (dd, 1H), 7.57 (d, 1H), 7.50 (d, 2H),7.42 (d, 2H), 7.32 (m, 1H), 7.24 (m, 1H), 7.12 (d, 1H), 7.05 (d, 1H),6.94 (m, 2H), 6.84 (d, 1H), 6.66 (dd, 1H), 6.35 (d, 1H), 6.25 (m, 2H),4.17 (t, 2H), 3.85 (m, 2H), 3.54 (m, 10H), 3.40 (m, 6H), 3.30 (s, 6H),3.02 (m, 2H), 2.96 (m, 4H), 2.28 (m, 4H), 1.88 (m, 1H), 1.60 (m, 2H),1.28 (m, 2H).

Example 1294-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 129A methyl2-(1H-indol-5-yloxy)-4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was made by substituting EXAMPLE 128B for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 150A for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 129B2-(1H-indol-5-yloxy)-4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was made by substituting EXAMPLE 129A for EXAMPLE 1D inEXAMPLE 1E.

Example 129C4-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was made by substituting EXAMPLE 129B for EXAMPLE 1E inEXAMPLE 27H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.38 (br s, 1H),11.19 (s, 1H), 10.00 (br s, 1H), 8.61 (t, 1H) 8.58 (d, 1H), 7.79 (dd,1H), 7.53 (m, 4H), 7.39 (m, 4H), 7.19 (m, 1H), 7.11 (m, 2H), 6.93 (d,1H), 6.84 (dd, 1H), 6.69 (dd, 1H), 6.39 (m, 1H), 6.19 (d, 1H), 4.40 (m,2H), 3.85 (m, 8H), 3.58 (m, 2H), 3.27 (m, 6H), 3.06 (m, 2H), 2.89 (s,6H), 1.89 (m, 1H), 1.60 (m, 2H), 1.27 (m, 2H).

Example 1304-(4-{[4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 130A methyl2-(1H-indol-4-yloxy)-4-(4-((4′-chloro-4-(2-morpholinoethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was made by substituting EXAMPLE 127A for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 130B2-(1H-indol-4-yloxy)-4-(4-((4′-chloro-4-(2-morpholinoethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was made by substituting EXAMPLE 130A for EXAMPLE 1D inEXAMPLE 1E.

Example 130C4-(4-{[4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was made by substituting EXAMPLE 130B for EXAMPLE 1E inEXAMPLE 27H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.47 (br s, 1H),11.23 (s, 1H), 8.59 (t, 1H) 8.47 (d, 1H), 7.63 (dd, 1H), 7.54 (d, 1H),7.47 (d, 2H), 7.27 (m, 6H), 7.13 (m, 2H), 7.03 (m, 1H), 6.93 (m, 1H),6.74 (dd, 1H), 6.35 (m, 1H), 6.24 (m, 1H), 4.39 (t, 2H), 3.85 (m, 6H),3.54 (m, 10H), 3.26 (m, 10H), 1.88 (m, 1H), 1.59 (m, 2H), 1.27 (m, 2H).

Example 1314-(4-{[4′-chloro-3-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 131A 4′-chloro-3-(2-morpholinoethoxy)biphenyl-2-carbaldehyde

This example was made by substituting EXAMPLE 128A for EXAMPLE 122B and4-(2-chloroethyl)morpholine hydrochloride salt for2-chloro-N,N-diemthylethanamine hydrochloride salt in EXAMPLE 122C.

Example 131B methyl2-(1H-indol-4-yloxy)-4-(4-((4′-chloro-3-(2-morpholinoethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was made by substituting EXAMPLE 131A for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 131C2-(1H-indol-4-yloxy)-4-(4-((4′-chloro-3-(2-morpholinoethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was made by substituting EXAMPLE 131B for EXAMPLE 1D inEXAMPLE 1E.

Example 131D4-(4-{[4′-chloro-3-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was made by substituting EXAMPLE 131C for EXAMPLE 1E inEXAMPLE 27H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.49 (br s, 1H),11.25 (s, 1H), 8.59 (t, 1H), 8.50 (d, 1H), 7.68 (dd, 1H), 7.52 (m, 4H),7.34 (d, 2H), 7.28 (m, 1H), 7.18 (m, 2H), 7.06 (d, 1H), 6.94 (m, 2H),6.73 (dd, 1H), 6.40 (d, 1H), 6.33 (d, 1H), 6.24 (m, 1H), 4.43 (t, 2H),3.85 (m, 10H), 3.61 (m, 6H), 3.27 (m, 8H), 3.02 (m, 2H), 1.88 (m, 1H),1.60 (m, 2H), 1.28 (m, 2H).

Example 1324-(4-{[4′-chloro-3-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 132A methyl2-(1H-indol-5-yloxy)-4-(4-((4′-chloro-3-(2-morpholinoethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was made by substituting EXAMPLE 131A for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 150A for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 132B2-(1H-indol-5-yloxy)-4-(4-((4′-chloro-3-(2-morpholinoethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was made by substituting EXAMPLE 132A for EXAMPLE 1D inEXAMPLE 1E.

Example 132C4-(4-{[4′-chloro-3-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was made by substituting EXAMPLE 132B for EXAMPLE 1E inEXAMPLE 27H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.34 (br s, 1H),11.17 (s, 1H), 8.60 (t, 1H), 8.58 (d, 1H), 7.79 (dd, 1H), 7.50 (m, 4H),7.39 (m, 4H), 7.19 (d, 1H), 7.14 (d, 1H), 7.09 (d, 1H), 6.93 (d, 1H),6.84 (dd, 1H), 6.69 (dd, 1H), 6.39 (m, 1H), 6.19 (d, 1H), 4.40 (m, 2H),3.85 (m, 6H), 3.48 (m, 8H), 3.27 (m, 10H), 3.06 (m, 2H), 1.89 (m, 1H),1.60 (m, 2H), 1.27 (m, 2H).

Example 1334-[4-({4′-chloro-4-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide

This example was made by substituting EXAMPLE 113D for EXAMPLE 27G andEXAMPLE 21A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.34 (d, 1H), 8.05 (d, 1H), 7.69 (dd, 1H), 7.59(d, 1H), 7.42 (m, 4H), 7.14 (m, 3H), 7.09 (d, 1H), 6.98 (d, 1H), 6.92(dd, 1H), 6.87 (m, 1H), 6.84 (m, 3H), 6.30 (d, 1H), 4.16 (t, 2H), 3.07(m, 6H), 2.95 (m, 4H), 2.56 (m, 2H), 2.45 (s, 3H), 2.35 (m, 4H), 2.03(m, 2H), 1.68 (m, 2H).

Example 1344-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamide

This example was made by substituting EXAMPLE 129B for EXAMPLE 27G andEXAMPLE 68F for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.34 (br s, 1H), 11.17 (s, 1H), 9.65 (br s,1H), 8.63 (t, 1H), 8.60 (d, 1H), 7.86 (dd, 1H), 7.53 (d, 2H), 7.41 (m,6H), 7.15 (m, 3H), 6.92 (m, 1H), 6.84 (dd, 1H), 6.66 (dd, 1H), 6.38 (m,1H), 6.16 (d, 1H), 4.37 (m, 2H), 3.50 (m, 12H), 3.17 (m, 4H), 2.97 (m,4H), 2.88 (s, 6H), 1.95 (m, 4H), 1.85 (m, 2H).

Example 1354-[4-({4′-chloro-4-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamide

This example was made by substituting EXAMPLE 126B for EXAMPLE 27G andEXAMPLE 68F for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.29 (br s, 1H), 11.16 (s, 1H), 9.56 (br s,1H), 8.63 (t, 1H), 8.60 (d, 1H), 7.85 (dd, 1H), 7.53 (d, 1H), 7.41 (m,4H), 7.32 (m, 3H), 7.24 (m, 1H), 7.12 (m, 3H), 6.84 (dd, 1H), 6.66 (dd,1H), 6.38 (m, 1H), 6.18 (d, 1H), 4.33 (t, 2H), 3.50 (m, 12H), 3.17 (m,4H), 2.97 (m, 4H), 2.86 (s, 6H), 1.95 (m, 4H), 1.85 (m, 2H).

Example 1364-(4-{[4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamide

This example was made by substituting EXAMPLE 127C for EXAMPLE 27G andEXAMPLE 68F for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.29 (br s, 1H), 11.16 (s, 1H), 9.54 (br s,1H), 8.63 (t, 1H), 8.60 (d, 1H), 7.85 (dd, 1H), 7.53 (d, 1H), 7.45 (d,2H), 7.38 (m, 2H), 7.31 (d, 2H), 7.23 (m, 2H), 7.12 (m, 3H), 6.84 (dd,1H), 6.66 (dd, 1H), 6.38 (m, 1H), 6.18 (d, 1H), 4.36 (t, 2H), 3.82 (m,4H), 3.50 (m, 8H), 3.17 (m, 10H), 2.98 (m, 4H), 1.95 (m, 6H), 1.85 (m,2H).

Example 1374-[4-({4′-chloro-4-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-N-[(3-nitro-4-{[1-(2,2,2-trifluoroethyl)piperidin-4-yl]amino}phenyl)sulfonyl]-2-phenoxybenzamide

This example was made by substituting EXAMPLE 113E for EXAMPLE 27G andEXAMPLE 108A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.71 (br s, 1H), 9.81 (br s, 1H), 8.46 (d, 1H),8.29 (d, 1H), 7.75 (dd, 1H), 7.50 (m, 3H), 7.30 (m, 4H), 7.21 (m, 3H),7.10 (m, 1H), 6.97 (m, 1H), 6.77 (m, 3H), 6.43 (s, 1H), 4.36 (t, 2H),3.72 (m, 2H), 3.58 (m, 4H), 3.23 (m, 6H), 2.95 (m, 4H), 2.89 (s, 6H),2.60 (m, 2H), 1.92 (m, 2H), 1.68 (m, 2H).

Example 1384-(4-{[4′-chloro-4-(2-pyrrolidin-1-ylethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamideExample 138A methyl4-(4-((4′-chloro-4-hydroxybiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoate

This example was made by substituting EXAMPLE 113B for EXAMPLE 68C and4-chlorophenylboronic acid for 4-methoxyphenylboronic acid in EXAMPLE68D.

Example 138B methyl4-(4-((4′-chloro-4-(2-(pyrrolidin-1-yl)ethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoate

This example was made by substituting EXAMPLE 138A for EXAMPLE 113B and1-(2-chloroethyl)pyrrolidine HCl salt for2-chloro-N,N-dimethylethanamine hydrochloride salt in EXAMPLE 113C.

Example 138C4-(4-((4′-chloro-4-(2-(pyrrolidin-1-yl)ethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoicacid

This example was made by substituting EXAMPLE 138B for EXAMPLE 1D inEXAMPLE 1E.

Example 138D4-(4-{[4′-chloro-4-(2-pyrrolidin-1-ylethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide

This example was made by substituting EXAMPLE 138C for EXAMPLE 1E inEXAMPLE 27H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.64 (br s, 1H),9.98 (br s, 1H), 8.62 (d, 1H), 8.47 (d, 1H), 7.75 (dd, 1H), 7.50 (m,3H), 7.26 (m, 6H), 7.14 (m, 2H), 6.99 (m, 1H), 6.81 (d, 2H), 6.77 (dd,1H), 6.43 (d, 1H), 4.36 (t, 2H), 3.86 (dd, 2H), 3.62 (m, 8H), 3.28 (m,8H), 3.10 (m, 4H), 2.04 (m, 2H), 1.90 (m, 3H), 1.65 (m, 2H), 1.29 (m,2H).

Example 1394-[4-({4′-chloro-4-[2-(diisopropylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamideExample 139A methyl4-(4-((4′-chloro-4-(2-(diisopropylamino)ethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoate

This example was made by substituting EXAMPLE 138A for EXAMPLE 113B and2-diisopropylaminoethyl chloride hydrochloride salt for2-chloro-N,N-dimethylethanamine hydrochloride salt in EXAMPLE 113C.

Example 139B4-(4-((4′-chloro-4-(2-(diisopropylamino)ethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoicacid

This example was made by substituting EXAMPLE 139A for EXAMPLE 1D inEXAMPLE 1E.

Example 139C4-[4-({4′-chloro-4-[2-(diisopropylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide

This example was made by substituting EXAMPLE 139B for EXAMPLE 1E inEXAMPLE 27H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.65 (br s, 1H),8.75 (br s, 1H), 8.62 (d, 1H), 8.47 (d, 1H), 7.75 (dd, 1H), 7.50 (m,3H), 7.31 (m, 4H), 7.23 (m, 2H), 7.13 (m, 2H), 6.99 (m, 1H), 6.79 (m,3H), 6.44 (m, 1H), 4.31 (t, 2H), 3.86 (dd, 2H), 3.62 (m, 10H), 3.28 (m,6H), 1.91 (m, 1H), 1.62 (m, 2H), 1.32 (m, 14H).

Example 1404-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(2,3-dihydro-1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

A suspension of EXAMPLE 40D (22.57 mg) and sodium cyanoborohydride (25mg) in acetic acid (5 ml) was stirred at room temperature for 2 hours.The product was partitioned between dichloromethane and water. Theorganic layer was separated, dried over Na₂SO₄, and concentrated. Thecrude product was purified by RP HPLC (C8, 30-100acetonitrile/water/0.1% trifluoroacetic acid). ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.56 (s, 1H), 9.60 (s, 1H), 8.66 (t, 1H), 8.57(d, 1H), 7.85 (dd, 1H), 7.71 (s, 1H), 7.46-7.60 (m, 5H), 7.29-7.42 (m,3H), 7.25 (d, 1H), 6.95 (s, 1H), 6.82 (s, 1H), 6.73 (d, 1H), 6.36 (s,1H), 4.32 (bs, 2H), 3.85 (dd, 4H), 3.59 (t, 4H), 3.35 (t, 2H), 3.27 (t,2H), 3.02 (t, 4H), 1.80-1.99 (m, 1H), 1.62 (d, 2H), 1.15-1.36 (m, 2H).

Example 1414-(4-{[2-(4-chlorophenyl)cyclohept-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamideExample 141A

(Z)-methyl 2-(trifluoromethylsulfonyloxy)cyclohept-1-enecarboxylate

This example was prepared by substituting methyl2-oxocycloheptanecarboxylate for5,5-dimethyl-2-methoxycarbonylcyclohexanone in EXAMPLE 18A.

Example 141B (Z)-methyl 2-(4-chlorophenyl)cyclohept-1-enecarboxylate

This example was prepared by substituting EXAMPLE 141A for EXAMPLE 18Ain EXAMPLE 18B.

Example 141C (Z)-(2-(4-chlorophenyl)cyclohept-1-enyl)methanol

This example was prepared by substituting EXAMPLE 141B for EXAMPLE 18Bin EXAMPLE 18C.

Example 141D (Z)-2-(4-chlorophenyl)cyclohept-1-enecarbaldehyde

This example was prepared by substituting EXAMPLE 141C for EXAMPLE 143Cin EXAMPLE 143D.

Example 141E (Z)-ethyl2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-enyl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 141D for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 141F(Z)-2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-enyl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 141E for EXAMPLE 143Ein EXAMPLE 143F.

Example 141G4-(4-{[2-(4-chlorophenyl)cyclohept-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 141F for EXAMPLE 1Eand EXAMPLE 68F for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.45 (m, 1H), 10.03 (m, 1H), 8.58 (m, 2H), 8.30(m, 1H), 7.26 (m, 11H), 6.25 (m, 2H), 3.14 (m, 12H), 2.73 (m, 5H), 1.94(m, 12H), 1.54 (m, 5H).

Example 1424-(4-{[2-(4-chlorophenyl)cyclooct-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamideExample 142A (Z)-ethyl2-(trifluoromethylsulfonyloxy)cyclooct-1-enecarboxylate

This example was prepared by substituting ethyl2-oxocyclooctanecarboxylate for5,5-dimethyl-2-methoxycarbonylcyclohexanone in EXAMPLE 18A.

Example 142B (Z)-ethyl 2-(4-chlorophenyl)cyclooct-1-enecarboxylate

This example was prepared by substituting EXAMPLE 142A for EXAMPLE 18Ain EXAMPLE 18B.

Example 142C (Z)-(2-(4-chlorophenyl)cyclooct-1-enyl)methanol

This example was prepared by substituting EXAMPLE 142B for EXAMPLE 18Bin EXAMPLE 18C.

Example 142D (Z)-2-(4-chlorophenyl)cyclooct-1-enecarbaldehyde

This example was prepared by substituting EXAMPLE 142C for EXAMPLE 143Cin EXAMPLE 143D.

Example 142E (Z)-ethyl2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)cyclooct-1-enyl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 142D for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 142F(Z)-2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)cyclooct-1-enyl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 142E for EXAMPLE 143Ein EXAMPLE 143F.

Example 142G4-(4-{[2-(4-chlorophenyl)cyclooct-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 142F for EXAMPLE 1Eand EXAMPLE 68F for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.51 (m, 1H), 10.01 (m, 1H), 8.58 (m, 2H), 7.26(m, 12H), 6.35 (m, 2H), 3.14 (m, 13H), 2.73 (m, 5H), 1.88 (m, 7H), 1.45(m, 10H).

Example 1434-(4-{[2-(4-chlorophenyl)cyclopent-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamideExample 143A ethyl2-(trifluoromethylsulfonyloxy)cyclopent-1-enecarboxylate

This example was prepared by substituting ethyl2-oxocyclopentanecarboxylate for5,5-dimethyl-2-methoxycarbonylcyclohexanone in EXAMPLE 18A.

Example 143B ethyl 2-(4-chlorophenyl)cyclopent-1-enecarboxylate

This example was prepared by substituting EXAMPLE 143A for EXAMPLE 18Ain EXAMPLE 18B.

Example 143C (2-(4-chlorophenyl)cyclopent-1-enyl)methanol

This example was prepared by substituting EXAMPLE 143B for EXAMPLE 18Bin EXAMPLE 18C.

Example 143D 2-(4-chlorophenyl)cyclopent-1-enecarbaldehyde

To a solution of oxalyl chloride (1.1 g) in dichloromethane (30 ml) at−78° C. was added dimethylsulfoxide (6.12 ml). The mixture was stirredat −78° C. for 30 minutes, and then a solution of EXAMPLE 143C (1.2 g)in dichloromethane (10 ml) was added. The mixture was stirred at −78° C.for 2 hours before the addition of triethylamine (10 ml). The mixturewas stirred overnight and the temperature was allowed to rise to roomtemperature. The mixture was diluted with ether (300 ml) and washed withwater, brine and dried over Na₂SO₄. Evaporation of solvent and columnpurification (5% ethyl acetate in hexane) to give the product.

Example 143E ethyl2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)cyclopent-1-enyl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 143D for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 143F2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)cyclopent-1-enyl)methyl)piperazin-1-yl)benzoicacid

To a solution of EXAMPLE 143E (254 mg) in tetrahydrofuran (4 ml),methanol (2 ml) and water (2 ml) was added LiOH—H₂O (126 mg). Themixture was stirred overnight. The mixture was then neutralized with 5%HCl and diluted with ethyl acetate (200 ml). After washing with brine,it was dried over Na₂SO₄. Evaporation of solvent gave the product.

Example 143G4-(4-{[2-(4-chlorophenyl)cyclopent-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3-pyrrolidin-1-ylpropyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 143F for EXAMPLE 1Eand EXAMPLE 68F for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d6) δ ppm 11.41 (m, 1H), 10.19 (m, 1H), 8.58 (m, 2H),7.26 (m, 14H), 6.33 (m, 2H), 3.80 (m, 4H), 3.13 (m, 12H), 2.69 (m, 5H),1.95 (m, 7H).

Example 1444-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 144A methyl 4,4-dimethyl-2-oxocyclopentanecarboxylate

This compound was prepared according to WO 2006/035061 (page 53).

Example 144B methyl4,4-dimethyl-2-(trifluoromethylsulfonyloxy)cyclopent-1-enecarboxylate

This example was prepared by substituting ethyl2-oxocyclopentanecarboxylate for5,5-dimethyl-2-methoxycarbonylcyclohexanone in EXAMPLE 18A.

Example 144C ethyl2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-enecarboxylate

This example was prepared by substituting EXAMPLE 144B for EXAMPLE 18Ain EXAMPLE 18B.

Example 144D (2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-enyl)methanol

This example was prepared by substituting EXAMPLE 144C for EXAMPLE 18Bin EXAMPLE 18C.

Example 144E 2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-enecarbaldehyde

This example was prepared by substituting EXAMPLE 144D for EXAMPLE 143Cin EXAMPLE 143D.

Example 144F ethyl2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-enyl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 144E for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 144G2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-enyl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 144F for EXAMPLE 143Ein EXAMPLE 143F.

Example 144H4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 144G for EXAMPLE 1Eand EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d6) δ 11.59 (m, 1H), 11.25 (s, 1H), 9.53 (m, 1H), 8.50(d, 1H), 8.16 (d, 1H), 8.16 (d, 1H), 7.80 (m, 1H), 7.56 (d, 1H), 7.26(m, 7H), 6.95 (m, 1H), 6.77 (dd, 1H), 6.41 (m, 2H), 6.23 (s, 1H), 2.87(m, 10H), 2.28 (m, 12H), 1.11 (m, 6H).

Example 1454-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 145A methyl 6,6-dimethyl-4-oxotetrahydro-2H-pyran-3-carboxylate

To a suspension of hexane-washed NaH (0.72 g, 60%) in tetrahydrofuran(30 ml) was added a solution of 2,2-dimethyldihydro-2H-pyran-4(3H)-one(2.0 g) in tetrahydrofuran (20 ml). The suspension was stirred for 30minutes. The dimethylcarbonate (6.31 ml) was added dropwise by syringe.The mixture was heated to reflux for 4 hours. The mixture was acidifiedwith 5% HCl and extracted with dichloromethane (3×100 ml) and washedwith water, brine and dried over Na₂SO₄. After evaporation, the crudeproduct was loaded on a column and eluted with 10% ethyl acetate inhexane to give the product.

Example 145B methyl6,6-dimethyl-4-(trifluoromethylsulfonyloxy)-5,6-dihydro-2H-pyran-3-carboxylate

This example was prepared by substituting EXAMPLE 145A for5,5-dimethyl-2-methoxycarbonylcyclohexanone in EXAMPLE 18A.

Example 145C methyl4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-carboxylate

This example was prepared by substituting EXAMPLE 145B for EXAMPLE 18Ain EXAMPLE 18B.

Example 145D(4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methanol

This example was prepared by substituting EXAMPLE 145C for EXAMPLE 18Bin EXAMPLE 18C.

Example 145E4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-carbaldehyde

This example was prepared by substituting EXAMPLE 145D for EXAMPLE 143Cin EXAMPLE 143D.

Example 145F ethyl2-(1H-indol-4-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 145E for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 145G2-(1H-indol-4-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 145F for EXAMPLE 143Ein EXAMPLE 143F.

Example 145H4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 145G for EXAMPLE 1Eand EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d6) δ 11.56 (m, 1H), 11.26 (s, 1H), 9.52 (m, 1H), 8.51(m, 1H), 8.16 (d, 1H), 7.80 (dd, 1H), 7.55 (d, 1H), 7.41 (d, 2H), 7.28(t, 1H), 7.17 (m, 4H), 6.96 (m, 2H), 6.74 (d, 1H), 6.39 (m, 2H), 6.23(s, 1H), 4.18 (s, 2H), 3.85 (m, 3H), 2.93 (m, 10H), 2.10 (m, 7H), 1.22(s, 6H).

Example 1464-(4-{[2-(4-chlorophenyl)cyclooct-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 142F for EXAMPLE 1Eand EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d6) δ 11.59 (s, 1H), 11.25 (s, 1H), 9.36 (m, 2H), 8.50(d, 1H), 8.16 (d, 1H), 7.79 (dd, 1H), 7.55 (d, 1H), 7.40 (d, 2H), 7.28(m, 1H), 7.14 (m, 5H), 6.96 (t, 1H), 6.74 (dd, 1H), 6.38 (m, 2H), 6.23(s, 1H), 2.91 (m, 14H), 2.27 (m, 6H), 1.49 (m, 11H).

Example 1474-(4-{[2-(4-chlorophenyl)cyclohept-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 141F for EXAMPLE 1Eand EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d6) δ 11.60 (s, 1H), 11.26 (s, 1H), 9.32 (m, 2H), 8.51(m, 1H), 8.16 (d, 1H), 7.79 (m, 1H), 7.55 (d, 1H), 7.39 (d, 2H), 7.29(t, 1H), 7.14 (m, 4H), 6.97 (t, 1H), 6.75 (dd, 1H), 6.40 (m, 2H), 6.22(s, 1H), 2.94 (m, 17H), 2.27 (m, 4H), 1.80 (m, 4H), 1.55 (m, 5H).

Example 1484-(4-{[2-(4-chlorophenyl)cyclopent-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 143F for EXAMPLE 1Eand EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d6) δ 11.60 (s, 1H), 11.26 (s, 1H), 9.47 (m, 2H), 8.51(m, 1H), 8.16 (d, 1H), 7.77 (m, 1H), 7.56 (d, 1H), 7.43 (d, 2H), 7.20(m, 6H), 6.96 (t, 1H), 6.77 (dd, 1H), 6.41 (m, 2H), 6.24 (s, 1H), 2.93(m, 17H), 2.01 (m, 8H).

Example 1494-(4-{[2-(4-chlorophenyl)cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 149A ethyl2-(trifluoromethylsulfonyloxy)cyclohex-1-enecarboxylate

This example was prepared by substituting ethyl2-oxocyclohexanecarboxylate for5,5-dimethyl-2-methoxycarbonylcyclohexanone in EXAMPLE 18A.

Example 149B ethyl 2-(4-chlorophenyl)cyclohex-1-enecarboxylate

This example was prepared by substituting EXAMPLE 149A for EXAMPLE 18Ain EXAMPLE 18B.

Example 149C (2-(4-chlorophenyl)cyclohex-1-enyl)methanol

This example was prepared by substituting EXAMPLE 149B for EXAMPLE 18Bin EXAMPLE 18C.

Example 149D 2-(4-chlorophenyl)cyclohex-1-enecarbaldehyde

This example was prepared by substituting EXAMPLE 149C for EXAMPLE 143Cin EXAMPLE 143D.

Example 149E ethyl2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared by substituting EXAMPLE 149D for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 149F2-(1H-indol-4-yloxy)-4-(4-((2-(4-chlorophenyl)cyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 149E for EXAMPLE 143Ein EXAMPLE 143F.

Example 149G4-(4-{[2-(4-chlorophenyl)cyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 149F for EXAMPLE 1Eand EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d6) δ 11.14 (s, 1H), 8.44 (d, 1H), 8.10 (d, 1H), 7.74(dd, 1H), 7.56 (d, 1H), 7.34 (d, 2H), 7.23 (m, 1H), 7.01 (m, 5H), 6.63(dd, 1H), 6.34 (d, 1H), 6.22 (m, 2H), 3.74 (m, 1H), 3.03 (m, 7H), 2.67(m, 5H), 2.07 (m, 11H), 1.67 (m, 7H).

Example 1504-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 150A methyl 2-(1H-indol-5-yloxy)-4-(piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 26A for EXAMPLE 1C andpiperazine for EXAMPLE 1B in EXAMPLE 1D.

Example 150B methyl2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 145E for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 150A for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 150C2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 150B for EXAMPLE 143Ein EXAMPLE 143F.

Example 150D4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 150C for EXAMPLE 1Eand EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d6) δ 11.00 (s, 1H), 8.42 (d, 1H), 8.07 (d, 1H), 7.67(dd, 1H), 7.52 (d, 1H), 7.37 (d, 2H), 7.29 (m, 1H), 7.14 (d, 2H), 6.93(d, 1H), 6.86 (d, 1H), 6.72 (dd, 1H), 6.55 (dd, 1H), 6.31 (s, 1H), 6.15(d, 1H), 5.85 (m, 3H), 4.11 (s, 2H), 3.00 (m, 8H), 2.82 (s, 2H), 2.73(m, 3H), 2.23 (m, 8H), 1.57 (m, 2H), 1.18 (s, 6H).

Example 1514-(4-{[2-(4-chlorophenyl)cyclohept-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 151A (Z)-methyl2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-enyl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 141D for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 150A for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 151B(Z)-2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)cyclohept-1-enyl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 151A for EXAMPLE 143Ein EXAMPLE 143F.

Example 151C4-(4-{[2-(4-chlorophenyl)cyclohept-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 151B for EXAMPLE 1Eand EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d6) δ 11.06 (s, 1H), 8.48 (d, 1H), 8.11 (d, 1H), 7.74(dd, 1H), 7.52 (d, 1H), 7.33 (m, 4H), 7.01 (m, 4H), 6.76 (dd, 1H), 6.58(dd, 1H), 6.34 (s, 1H), 6.14 (d, 1H), 5.75 (s, 1H), 3.69 (m, 1H), 2.96(m, 6H), 2.71 (m, 2H), 2.36 (m, 8H), 2.21 (s, 5H), 1.98 (m, 2H), 1.63(m, 8H).

Example 1524-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide

This compound was made by substituting EXAMPLE 18G for EXAMPLE 1E andEXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 8.43 (m, 1H) 8.18 (d, 1H) 7.82 (dd, 1H) 7.52 (d,1H) 7.40 (m, 2H) 7.22 (m, 3H) 7.11 (m, 2H) 7.01 (t, 1H) 6.79 (m, 3H)6.45 (d, 1H) 3.06 (m, 14H) 2.20 (m, 4H) 2.04 (s, 3H) 1.85 (m, 2H) 1.47(m, 2H) 0.96 (s, 6H).

Example 1534-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[2-(dimethylamino)ethyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamideExample 153A 4-(2-(dimethylamino)ethylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting N,N-dimethylethylenediaminefor (tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 153B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[2-(dimethylamino)ethyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 153A for EXAMPLE 1Fand EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.75 (br s, 1H), 9.78 (br s, 1H), 9.44 (br s,1H), 8.66 (t, 1H), 8.49 (d, 1H), 7.83 (d, 1H), 7.70 (m, 2H), 7.51 (m,4H), 7.38 (d, 2H), 7.33 (m, 1H), 7.24 (d, 2H), 7.18 (d, 1H), 7.02 (dd,1H), 6.81 (d, 2H), 6.76 (d, 1H), 6.44 (s, 1H), 4.30 (m, 1H), 3.83 (m,4H), 3.31 (m, 6H), 3.15 (m, 2H), 3.04 (m, 2H), 2.85 (s, 6H).

Example 1544-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamideExample 154A 4-(3-(dimethylamino)propylamino)-3-nitrobenzenesulfonamide

This example was prepared by substitutingN,N-dimethyl-1,3-propanediamine for (tetrahydropyran-4-yl)methylamine inEXAMPLE 1F.

Example 154B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 154A for EXAMPLE 1Fand EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.68 (br s, 1H), 9.38 (br s, 1H), 8.66 (t, 1H),8.49 (d, 1H), 7.80 (d, 1H), 7.68 (m, 2H), 7.51 (m, 4H), 7.38 (d, 1H),7.33 (m, 2H), 7.24 (d, 2H), 7.16 (d, 1H), 7.02 (dd, 1H), 6.81 (d, 2H),6.76 (d, 1H), 6.43 (s, 1H), 4.25 (m, 1H), 3.50 (m, 4H), 3.30 (m, 4H),3.12 (m, 6H), 2.78 (s, 6H), 1.95 (m, 2H).

Example 1554-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 7A for EXAMPLE 1F andEXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.70 (br s, 1H), 9.72 (br s, 1H), 8.68 (t, 1H),8.49 (d, 1H), 7.81 (d, 1H), 7.70 (m, 2H), 7.51 (m, 4H), 7.37 (d, 2H),7.33 (m, 1H), 7.24 (d, 2H), 7.15 (d, 1H), 7.03 (dd, 1H), 6.81 (d, 2H),6.76 (d, 1H), 6.44 (s, 1H), 4.24 (m, 1H), 3.97 (m, 2H), 3.63 (m, 4H),3.28 (m, 4H), 3.18 (m, 4H), 3.06 (m, 4H), 2.88 (m, 4H), 1.99 (m, 2H).

Example 1564-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[4-(dimethylamino)butyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamideExample 156A 4-(4-(dimethylamino)butylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting N,N-dimethyl-1,4-butanediaminefor (tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 156B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[4-(dimethylamino)butyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 156A for EXAMPLE 1Fand EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.70 (br s, 1H), 9.34 (br s, 1H), 8.63 (t, 1H),8.48 (d, 1H), 7.79 (d, 1H), 7.70 (m, 2H), 7.51 (m, 4H), 7.39 (d, 2H),7.33 (m, 1H), 7.24 (d, 2H), 7.12 (d, 1H), 7.01 (dd, 1H), 6.80 (d, 2H),6.75 (d, 1H), 6.44 (s, 1H), 4.28 (m, 1H), 3.83 (m, 4H), 3.45 (m, 10H),3.10 (m, 4H), 2.85 (s, 6H), 1.66 (m, 4H).

Example 1574-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{[1-(phenylsulfonyl)piperidin-4-yl]amino}phenyl)sulfonyl]-2-phenoxybenzamideExample 157A tert-butyl4-(2-nitro-4-sulfamoylphenylamino)piperidine-1-carboxylate

This example was prepared by substituting 1-Boc-4-aminopiperidine for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 157B 3-nitro-4-(piperidin-4-ylamino)benzenesulfonamide

This example was prepared by substituting EXAMPLE 157A for EXAMPLE 1A inEXAMPLE 1B.

Example 157C3-nitro-4-(1-(phenylsulfonyl)piperidin-4-ylamino)benzenesulfonamide

A mixture of EXAMPLE 157B (84 mg), benzenesulfonyl chloride (46 mg), andtriethylamine (101 mg) in CH₂Cl₂ (2 mL) was stirred for 1 hours. Theproduct was chromatographed on silica gel with 25% ethylacetate/hexanes.

Example 157D4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{[1-(phenylsulfonyl)piperidin-4-yl]amino}phenyl)sulfonyl]-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 157C for EXAMPLE 1Fand EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.68 (br s, 1H), 9.65 (br s, 1H), 8.42 (s, 1H),8.19 (d, 1H), 7.78 (m, 2H), 7.70 (m, 4H), 7.51 (m, 5H), 7.37 (m, 3H),7.19 (m, 3H), 6.94 (dd, 1H), 6.75 (m, 3H), 6.44 (s, 1H), 4.28 (m, 1H),3.73 (m, 4H), 3.50 (m, 4H), 3.17 (m, 2H), 3.03 (m, 2H), 2.86 (m, 2H),1.99 (m, 2H), 1.74 (m, 2H).

Example 1584-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{[1-(quinolin-8-ylsulfonyl)piperidin-4-yl]amino}phenyl)sulfonyl]-2-phenoxybenzamideExample 158A3-nitro-4-(1-(quinolin-8-ylsulfonyl)piperidin-4-ylamino)benzenesulfonamide

This example was prepared by substituting quinoline-8-sulfonyl chloridefor benzenesulfonyl chloride in EXAMPLE 157C.

Example 158B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{[1-(quinolin-8-ylsulfonyl)piperidin-4-yl]amino}phenyl)sulfonyl]-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 158A for EXAMPLE 1Fand EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.66 (br s, 1H), 9.10 (dd, 1H), 8.55 (s, 1H),8.41 (m, 2H), 8.32 (d, 1H), 8.20 (d, 1H), 7.78 (dd, 2H), 7.72 (d, 2H),7.48 (m, 4H), 7.39 (dd, 2H), 7.33 (m, 1H), 7.17 (m, 3H), 6.95 (dd, 1H),6.76 (m, 3H), 6.42 (s, 1H), 4.35 (m, 1H), 3.90 (d, 2H), 3.77 (m, 2H),3.34 (m, 6H), 2.99 (m, 4H), 1.97 (m, 2H), 1.65 (m, 2H).

Example 1594-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-phenoxy-N-({4-{[1-(phenylsulfonyl)piperidin-4-yl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamideExample 159A (2-fluorophenyl)(trifluoromethyl)sulfane

Methyl viologen hydrochloride (1.17 g) in N,N-dimethylformamide (80 mL)at 25° C. was saturated with trifluoromethyl iodide, treated with2-fluorobenzenethiol (9.7 mL) and triethylamine (20 mL), stirred for 24hours, diluted with water (240 mL) and extracted with diethyl ether. Theextract was washed with 1M NaOH, saturated ammonium chloride and brineand concentrated.

Example 159B 1-fluoro-2-(trifluoromethylsulfonyl)benzene

EXAMPLE 159A (17.346 g) in 1:1:2 carbon tetrachloride:acetonitrile:water(800 mL) at 25° C. was treated with sodium periodate (56.8 g) andruthenium(III) chloride hydrate (183 mg), stirred for 18 hours, dilutedwith dichloromethane (100 mL) and filtered through diatomaceous earth(Celite®). The filtrate was washed with saturated sodium bicarbonate andextracted with dichloromethane. The extract was washed with brine anddried (MgSO₄), filtered and concentrated. The concentrate was filteredthrough silica gel.

Example 159C 4-fluoro-3-(trifluoromethylsulfonyl)benzenesulfonamide

EXAMPLE 159B (37.3 g) in chlorosulfonic acid (32.8 mL) at 120° C. wasstirred for 18 hours, cooled to 25° C. and pipetted onto crushed ice.The mixture was extracted with ethyl acetate, and the extract was washedwith water and brine and dried (MgSO₄), filtered and concentrated. Thecrude product was taken up in isopropanol (706 mL) at −78° C., treatedwith ammonium hydroxide (98 mL) over 1 hour, stirred for 1 hour,quenched with 6M HCl (353 mL), warmed to 25° C. and concentrated. Theconcentrate was mixed with water and extracted with ethyl acetate. Theextract was dried over MgSO₄, filtered and concentrated. The concentratewas recrystallized from ethyl acetate/hexane.

Example 159D tert-butyl4-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)piperidine-1-carboxylate

This example was prepared by substituting 1-Boc-4-aminopiperidine for(tetrahydropyran-4-yl)methylamine and EXAMPLE 159C for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 1F.

Example 159E4-(piperidin-4-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

This example was prepared by substituting EXAMPLE 159D for EXAMPLE 1A inEXAMPLE 1B.

Example 159F4-(1-(phenylsulfonyl)piperidin-4-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

This example was prepared by substituting EXAMPLE 159E for EXAMPLE 157Bin EXAMPLE 157C.

Example 159G4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-phenoxy-N-({4-{[1-(phenylsulfonyl)piperidin-4-yl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 159F for EXAMPLE 1Fand EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.72 (br s, 1H), 9.70 (br s, 1H), 8.07 (s, 1H),7.67-7.82 (m, 7H), 7.52 (d, 2H), 7.47 (d, 2H), 7.36 (m, 3H), 7.24 (dd,2H), 7.14 (d, 1H), 7.01 (m, 1H), 6.78 (d, 2H), 6.72 (m, 2H), 6.44 (d,1H), 4.27 (m, 1H), 3.73 (m, 4H), 3.46 (m, 4H), 3.17 (m, 2H), 3.03 (m,2H), 2.87 (m, 2H), 1.97 (m, 2H), 1.64 (m, 2H).

Example 1604-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-phenoxy-N-({4-{[1-(quinolin-8-ylsulfonyl)piperidin-4-yl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamideExample 160A4-(1-(quinolin-8-ylsulfonyl)piperidin-4-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

This example was prepared by substituting EXAMPLE 159E for EXAMPLE 157Band quinoline-8-sulfonyl chloride for benzenesulfonyl chloride inEXAMPLE 157C.

Example 160B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-phenoxy-N-({4-{[1-(quinolin-8-ylsulfonyl)piperidin-4-yl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 160A for EXAMPLE 1Fand EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.74 (br s, 1H), 9.50 (br s, 1H), 9.08 (dd,1H), 8.55 (s, 1H), 8.39 (d, 1H), 8.33 (d, 1H), 8.06 (s, 1H), 7.82 (dd,2H), 7.70 (m, 1H), 7.50 (m, 3H), 7.40 (dd, 2H), 7.33 (m, 1H), 7.21 (m,2H), 7.08 (m, 2H), 6.99 (dd, 1H), 6.95 (s, 1H), 6.78 (d, 1H), 6.73 (m,2H), 6.42 (s, 1H), 4.35 (m, 1H), 3.75 (m, 4H), 3.34 (m, 6H), 3.05 (m,4H), 1.93 (m, 2H), 1.55 (m, 2H.

Example 1614-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[(1S)-3-(dimethylamino)-1-thien-2-ylpropyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamideExample 161A (S)-3-(benzyloxycarbonylamino)-3-(thiophen-2-yl)propanoicacid

(S)-3-amino-3-(thiophen-2-yl)propanoic acid (0.894 g) andbenzyloxycarbonyl chloride 0.980 g) were stirred in 2M NaOH (8 mL) anddioxane (26 mL) at 0° C. for 24 hours. The reaction mixture wasacidified with concentrated aqueous HCl, extracted twice with ethylacetate, and the extracts were dried over MgSO₄, filtered, concentrated,and chromatographed on silica gel with 50% ethyl acetate/hexanes.

Example 161B (S)-benzyl3-(dimethylamino)-3-oxo-1-(thiophen-2-yl)propylcarbamate

This example was prepared by substituting EXAMPLE 161A for EXAMPLE 1Eand dimethylamine for EXAMPLE 1F in EXAMPLE 1G.

Example 161C (S)—N¹,N¹-dimethyl-3-(thiophen-2-yl)propane-1,3-diamine

A solution of EXAMPLE 161B (400 mg) and borane in tetrahydrofuran (1M,2.5 mL) in tetrahydrofuran (6 mL) was stirred for 24 hours. The reactionwas quenched with methanol, taken up in pH 7 buffer solution, andextracted three times with ethyl acetate. The combined extracts werewashed with brine and concentrated. The crude product was taken up inHBr in acetic acid (1.1 mL) and stirred for 2 hours. The reaction waspoured into CH₂Cl₂ (50 mL) and washed with 1M NaOH solution. The organiclayer was dried over Na₂SO₄, and concentrated.

Example 161D(S)-4-(3-(dimethylamino)-1-(thiophen-2-yl)propylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting EXAMPLE 161C for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 161E4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[(1S)-3-(dimethylamino)-1-thien-2-ylpropyl]amino}-3-nitrophenyl)sulfonyl]-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 161D for EXAMPLE 1Fand EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆/D₂O) δ 11.72 (br s, 1H), 9.51 (br s, 1H), 8.60 (d,1H), 8.48 (s, 1H), 7.75 (d, 1H), 7.70 (m, 1H), 7.51 (m, 4H), 7.38 (d,2H), 7.32 (m, 1H), 7.25 (d, 1H), 7.16 (m, 3H), 7.06 (d, 1H), 6.92 (m,1H), 6.75 (d, 3H), 6.44 (d, 1H), 5.31 (m, 1H), 4.30 (m, 1H), 3.54 (m,8H), 3.20 (m, 2H), 3.07 (m, 2H), 2.80 (s, 6H), 2.35 (m, 2H).

Example 1624-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(thien-2-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamideExample 162A 3-nitro-4-(thiophen-2-ylmethylamino)benzenesulfonamide

This example was prepared by substituting 2-thiophenemethylamine for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 162B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(thien-2-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 162B for EXAMPLE 1Fand EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆/D₂O) δ 11.67 (br s, 1H), 9.55 (br s, 1H), 9.11 (t,1H), 8.47 (s, 1H), 7.70 (m, 2H), 7.51 (m, 4H), 7.38 (d, 2H), 7.33 (m,1H), 7.15 (m, 4H), 7.02 (d, 1H), 6.94 (m, 1H), 6.74 (d, 3H), 6.44 (d,1H), 4.87 (m, 2H), 4.37 (m, 1H), 3.34 (m, 8H), 3.03 (m, 2H).

Example 1634-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamideExample 163A4-((tetrahydro-2H-pyran-4-yl)methylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

This example was prepared by substituting EXAMPLE 159C for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 1F.

Example 163B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 163A for EXAMPLE 1Fand EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.71 (br s, 1H), 8.10 (d, 1H), 7.86 (d, 1H),7.10 (m, 1H), 7.50 (m, 4H), 7.37 (m, 2H), 7.27 (m, 3H), 7.08 (m, 1H),7.03 (dd, 1H), 6.95 (d, 1H), 6.82 (d, 1H), 6.76 (d, 1H), 6.43 (s, 1H),4.35 (m, 1H), 3.84 (dd, 2H), 3.35 (m, 8H), 3.22 (m, 2H), 3.03 (m, 2H),2.86 (m, 2H), 1.86 (m, 1H), 1.55 (m, 2H), 1.26 (m, 2H).

Example 1644-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{[2-(1H-1,2,3-triazol-1-yl)ethyl]amino}phenyl)sulfonyl]-2-phenoxybenzamideExample 164A 4-(2-hydroxyethylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting 2-aminoethanol for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 164B4-(2-(tert-butyldimethylsilyloxy)ethylamino)-3-nitrobenzenesulfonamide

EXAMPLE 164A (131 mg), t-butyldimethylsilyl chloride (75 mg) andimidazole (68 mg) were stirred in CH₂Cl₂ (17 mL) for 24 hours. Thereaction mixture was chromatographed on silica gel with 10% ethylacetate/hexanes.

Example 164CN-(4-(2-(tert-butyldimethylsilyloxy)ethylamino)-3-nitrophenylsulfonyl)-4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 164B for EXAMPLE 1F inEXAMPLE 1G.

Example 164D2-(4-(N-(4-(4-((4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxybenzoyl)sulfamoyl)-2-nitrophenylamino)ethyl4-methylbenzenesulfonate

EXAMPLE 164C (150 mg) and concentrated aqueous HCl (0.020 mL) werestirred in tetrahydrofuran (1 mL) and methanol (1 mL) for 1 hours. Themixture was filtered through a short silica gel column. The product wastaken up in CH₂Cl₂ (1 mL) and to it was added triethylamine (0.074 mL)and p-toluenesulfonic anhydride (58 mg) and the reaction was stirred for24 hours. The reaction mixture was chromatographed on silica gel with10% ethyl acetate/hexanes.

Example 164E4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{[2-(1H-1,2,3-triazol-1-yl)ethyl]amino}phenyl)sulfonyl]-2-phenoxybenzamide

EXAMPLE 164D (30 mg), 1,2,3-triazole (7 mg) and cesium carbonate (55 mg)were stirred in N,N-dimethylformamide (0.2 mL) for 24 hours. Thereaction was quenched with ammonium chloride, and was extracted twicewith ethyl acetate. The combined organic layers were dried over MgSO₄,filtered, and concentrated. The product was purified by preparative HPLCusing a C18 column, 250×50 mm, 10μ, and eluting with a gradient of20-100% CH₃CN vs. 0.1% trifluoroacetic acid in water, giving the productas a trifluoroacetate salt. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ11.75 (br s, 1H), 9.62 (br s, 1H), 8.66 (dd, 1H), 8.44 (d, 1H), 8.18 (s,1H), 7.72 (m, 3H), 7.51 (m, 5H), 7.36 (m, 3H), 7.19 (dd, 2H), 7.06 (m,1H), 6.93 (dd, 1H), 6.75 (d, 2H), 6.45 (s, 1H), 4.70 (t, 2H), 3.93 (dt,2H), 3.61 (m, 4H), 3.22 (m, 2H), 3.01 (m, 2H), 2.84 (m, 2H).

Example 1654-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{[2-(2H-1,2,3-triazol-2-yl)ethyl]amino}phenyl)sulfonyl]-2-phenoxybenzamide

This example was prepared in the same reaction as that for EXAMPLE 164E.¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.75 (br s, 1H), 9.70 (br s,1H), 8.67 (dd, 1H), 8.42 (s, 1H), 7.80 (s, 1H), 7.75 (m, 1H), 7.68 (d,2H), 7.51 (m, 5H), 7.37 (m, 3H), 7.18 (dd, 2H), 6.97 (m, 1H), 6.92 (dd,1H), 6.75 (d, 2H), 6.46 (s, 1H), 4.76 (t, 2H), 3.93 (dt, 2H), 3.67 (m,4H), 3.22 (m, 2H), 3.03 (m, 2H), 2.84 (m, 2H).

Example 1664-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(4-{[3-(dimethylamino)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(2-naphthyloxy)benzamide

This example was prepared by substituting EXAMPLE 35B for EXAMPLE 27Gand EXAMPLE 154A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.83 (br s, 1H), 9.46 (br s, 1H), 8.53 (t, 1H),8.40 (s, 1H), 7.81 (d, 2H), 7.71 (m, 1H), 7.63 (m, 2H), 7.51 (m, 5H),7.37 (m, 4H), 7.17 (d, 1H), 7.03 (s, 1H), 6.82 (d, 2H), 6.57 (d, 1H),4.27 (m, 1H), 3.62 (m, 6H), 3.39 (m, 2H), 3.09 (m, 2H), 2.80-3.25 (m,6H), 2.79 (s, 6H), 1.91 (m, 2H).

Example 1674-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{[2-(2-oxopyridin-1(2H)-yl)ethyl]amino}phenyl)sulfonyl]-2-phenoxybenzamide

This example was prepared by substituting pyridin-2-ol for1,2,3-triazole in EXAMPLE 164E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ11.70 (br s, 1H), 9.65 (br s, 1H), 8.75 (t, 1H), 8.44 (d, 1H), 7.72 (d,2H), 7.64 (d, 1H), 7.51 (m, 5H), 7.37 (m, 3H), 7.20 (m, 3H), 6.95 (t,1H), 6.77 (d, 3H), 6.46 (s, 1H), 6.41 (d, 1H), 6.21 (t, 1H), 4.31 (m,1H), 4.17 (t, 2H), 3.74 (dt, 2H), 3.60 (m, 6H), 3.20 (m, 2H), 3.03 (m,2H), 2.87 (m, 2H).

Example 1684-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-[(3-nitro-4-{[2-(pyridin-2-yloxy)ethyl]amino}phenyl)sulfonyl]-2-phenoxybenzamide

This example was prepared by substituting pyridin-2-ol for1,2,3-triazole in EXAMPLE 164E. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ11.71 (br s, 1H), 9.65 (br s, 1H), 8.84 (t, 1H), 8.44 (d, 1H), 8.19 (d,1H), 7.74 (m, 3H), 7.51 (m, 5H), 7.37 (m, 3H), 7.20 (m, 3H), 7.00 (dd,1H), 6.92 (t, 1H), 6.83 (d, 1H), 6.76 (m, 2H), 6.45 (d, 1H), 4.56 (t,2H), 4.31 (m, 1H), 3.81 (dt, 2H), 3.71 (m, 6H), 3.23 (m, 2H), 3.04 (m,2H), 2.89 (m, 2H).

Example 1694-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(2-pyridin-4-ylethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamideExample 169A 3-nitro-4-(2-(pyridin-4-yl)ethylamino)benzenesulfonamide

This example was prepared by substituting 2-(pyridin-4-yl)ethanamine for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1E.

Example 169B4-{4-[(4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-N-({3-nitro-4-[(2-pyridin-4-ylethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide

This example was prepared by substituting EXAMPLE 169A for EXAMPLE 1Fand EXAMPLE 1E for EXAMPLE 27G in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.71 (br s, 1H), 9.70 (br s, 1H), 8.69 (d, 1H),8.61 (t, 1H), 8.46 (s, 1H), 7.79 (dd, 1H), 7.72 (d, 3H), 7.51 (m, 5H),7.37 (d, 2H), 7.32 (d, 1H), 7.21 (m, 3H), 6.95 (t, 1H), 6.78 (d, 2H),6.75 (d, 1H), 6.44 (d, 1H), 4.23 (m, 1H), 3.76 (dt, 2H), 3.63 (m, 4H),3.13 (t, 2H), 2.76-3.24 (m, 6H).

Example 1704-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-{[3-(dimethylamino)propyl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamideExample 170A4-(3-(dimethylamino)propylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

This example was prepared by substitutingN,N-dimethyl-1,3-propanediamine for (tetrahydropyran-4-yl)methylamineand EXAMPLE 159C for 4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 1F.

Example 170B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-{[3-(dimethylamino)propyl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 170A for EXAMPLE 1Fand EXAMPLE 26C for EXAMPLE 27G in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.42 (br s, 1H), 11.17 (s, 1H), 9.37 (br s,1H), 8.22 (d, 1H), 7.98 (d, 1H), 7.52 (d, 1H), 7.35-7.45 (m, 4H), 7.19(d, 1H), 7.08 (m, 3H), 6.85 (dd, 1H), 6.67 (dd, 1H), 6.40 (d, 1H), 6.19(d, 1H), 3.55 (m, 8H), 3.04 (m, 4H), 2.77 (s, 6H), 2.72 (m, 2H), 2.17(m, 2H), 2.00 (m, 2H), 1.88 (m, 2H), 1.44 (m, 2H), 0.93 (s, 6H).

Example 1714-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-{[3-(dimethylamino)propyl]amino}-3-(trifluoromethyl)phenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 27Gand EXAMPLE 92B for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.19 (br s, 1H), 9.33 (br s, 1H), 7.94 (d, 1H),7.85 (d, 1H), 7.54 (d, 1H), 7.35-7.45 (m, 4H), 7.20 (d, 1H), 7.07 (d,2H), 6.88 (dd, 2H), 6.67 (dd, 1H), 6.58 (m, 1H), 6.41 (s, 1H), 6.18 (s,1H), 3.57 (m, 6H), 3.33 (m, 2H), 3.09 (m, 2H), 3.04 (m, 2H), 2.77 (s,6H), 2.74 (m, 2H), 2.17 (m, 2H), 2.00 (m, 2H), 1.87 (m, 2H), 1.44 (m,2H), 0.93 (s, 6H).

Example 1724-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-cyano-4-{[3-(dimethylamino)propyl]amino}phenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 27Gand EXAMPLE 90B for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.19 (br s, 1H), 9.38 (br s, 1H), 7.98 (s, 1H),7.81 (d, 1H), 7.55 (d, 1H), 7.35-7.45 (m, 4H), 7.20 (s, 1H), 7.16 (t,1H), 7.07 (d, 2H), 6.86 (dd, 2H), 6.68 (dd, 1H), 6.41 (s, 1H), 6.18 (s,1H), 3.57 (m, 6H), 3.31 (m, 2H), 3.09 (m, 2H), 3.04 (m, 2H), 2.77 (s,6H), 2.74 (m, 2H), 2.17 (m, 2H), 2.00 (m, 2H), 1.87 (m, 2H), 1.44 (m,2H), 0.93 (s, 6H).

Example 1734-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamideExample 173A tert-butyl1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylcarbamate

A mixture of tert-butyl piperidin-4-ylcarbamate (45 g) anddihydro-2H-pyran-4(3H)-one (24.74 g) in dichloromethane (1000 mL) wastreated with sodium triacetoxyborohydride (61.9 g), stirred at roomtemperature for 16 hours, washed with 1M sodium hydroxide and dried withanhydrous sodium sulfate, filtered and concentrated. The concentrate wasflash column chromatographed on silica gel with 10-20%methanol/dichloromethane.

Example 173B 1-(tetrahydro-2H-pyran-4-yl)piperidin-4-amine

A solution of EXAMPLE 173A (52.57 g) in dichloromethane (900 mL) wastreated with 4M HCl (462 mL), mixed vigorously at room temperature for16 hours and concentrated.

Example 173C3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)benzenesulfonamide

A mixture of EXAMPLE 173B (22.12 g), water (43 mL), and triethylamine(43.6 mL) in 1,4-dioxane (300 mL) was stirred at room temperature untilEXAMPLE 173B completely dissolved. The solution was then treated with4-chloro-3-nitrobenzenesulfonamide, heated at 90° C. for 16 hours,cooled and concentrated. 10% methanol in dichloromethane was added, andthe solution was stirred vigorously at room temperature until a finesuspension existed and the mixture was filtered.

Example 173D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

A mixture of EXAMPLE 26C (3.95 g), EXAMPLE 173C (2.66 g),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (2.66 g),and 4-dimethylaminopyridine (0.846 g) in dichloromethane (70 mL) andacetonitrile (20 mL) was stirred at 35° C. for 24 hours, cooled andchromatographed on silica gel with 0-10% methanol in ethyl acetate, then10% methanol in 1:1 ethyl acetate/dichloromethane. The combinedfractions were concentrated, dissolved in of 5% methanol/ethyl acetate(1.5 L), and the solution was washed with saturated NaH₂PO₄ solution andbrine and dried over Na₂SO₄, filtered, concentrated to 300 mL, cooled,and filtered. The remaining solution was concentrated partway andfiltered again to isolate more product. ¹H NMR (300 MHz,dimethysulfoxide-d₆) δ 11.17 (brs, 1H), 10.70 (br s, 1H), 8.60 (d, 1H),8.20 (br d, 1H), 7.88 (dd, 1H), 7.50 (d, 1H), 7.39 (m, 2H), 7.33 (d,2H), 7.16 (m, 2H), 7.03 (d, 2H), 6.85 (dd, 1H), 6.65 (dd, 1H), 6.39 (s,1H), 6.14 (s, 1H), 3.97 (m, 4H), 3.44 (m, 4H), 3.04 (m, 6H), 2.75 (m,2H), 2.14 (m, 8H), 1.95 (m, 6H), 1.66 (m, 2H), 1.38 (t, 2H), 0.92 (s,6H).

Example 1744-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 174A 4-(4-methylpiperazin-1-ylamino)-3-nitrobenzenesulfonamide

A mixture of 4-chloro-3-nitrobenzenesulfonamide (1 g),4-methylpiperazin-1-amine dihydrochloride (1 g) andN,N,N²,N²-tetramethylethane-1,2-diamine (3 mL) in dioxane (10 mL) wasrefluxed for 12 hours, cooled to ambient temperature and filtered. Thefiltrate was added to a silica gel column (Analogix, SF65-200g) andpurified by eluting with 1-5% methanol/dichloromethane).

Example 174B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

A mixture of EXAMPLE 26C (0.108 g), EXAMPLE 174A (64 mg),1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (0.08 g)and 4-dimethylaminopyridine (0.08 g) in dichloromethane (3 mL) wasstirred at ambient temperature overnight and concentrated. Theconcentrate was added to a preparative HPLC column and eluted with20-100% acetonitrile/water with 0.1% trifluoroacetic acid. Thetrifluoroacetic acid salt solution was neutralized with NaHCO₃ andextracted with dichloromethane. This solution was washed with saturatedNaHCO₃, dried over Na₂SO₄, and filtered and concentrated. ¹H NMR (500MHz, dimethysulfoxide-d₆) δ 11.14 (s, 1H), 9.17 (s, 1H), 8.52 (s, 1H),7.83 (m, 1H), 7.53 (m, 2H), 7.36 (m, 4H), 7.12 (s, 1H), 7.03 (d, 2H),6.83 (m, 1H), 6.62 (m, 1H), 6.38 (s, 1H), 6.13 (m, 1H), 5.76 (s, 2H),2.85 (m, 12H), 2.35 (m, 4H), 2.14 (m, 6H), 1.94 (m, 2H), 1.38 (m, 2H),0.92 (s, 6H).

Example 1754-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 175A 1-(4′-chlorobiphenyl-2-yl)ethanone

A mixture of 1-(2-bromophenyl)ethanone (3.1 g, 15.57mmol)-4-chlorophenylboronic acid (2.92 g), (Ph₃P)₂PdCl₂(bis(triphenylphosphine)palladium(II) dichloride) (1.202 g) and Na₂CO₃(3.30 g) in dimethoxyethane-ethanol-water (7:2:3, 50 mL) was heated at100° C. for 3 hours and concentrated. The concentrate was suspended indichloromethane (30 mL) and the insoluble material was removed byfiltration. The filtrate was loaded onto a silica gel column, elutedwith 0%-50% dichloromethane in hexane to provide the title compound.

Example 175B tert-butyl4-(1-(4′-chlorobiphenyl-2-yl)ethyl)piperazine-1-carboxylate

EXAMPLE 175A (1.9 g) was dissolved in dichloromethane (3 mL) andtitanium(IV) chloride (9.06 mL, 9.06 mmol) was added. The solution wascooled to 0° C. and tert-butyl piperazine-1-carboxylate (3.07 g) wasadded. The resulting mixture was stirred at ambient temperature for 3hours and NaCNBH₃ (0.828 g) in methanol (5 mL) was added. The resultingmixture was stirred at room temperature overnight and neutralized byaqueous NaOH, and then concentrated. To the concentrate was added ethylacetate and the insoluble material was filtered off. The organic layerwas washed with water and concentrated. The concentrate was dissolved ina mixture of methanol-trifluoroacetic acid-dimethysulfoxide, loaded ontoa reverse phase C18 column, and eluted with 0-80% acetonitrile in 0.1%trifluoroacetic acid water over 70 minutes.

Example 175C 1-(1-(4′-chlorobiphenyl-2-yl)ethyl)piperazine

To a solution of EXAMPLE 175B (650 mg) in dichloromethane (6 mL) wasadded trifluoroacetic acid (6 mL) at 0° C. The reaction mixture wasstirred at 0° C. for 50 minutes and concentrated. The concentrate wasdissolved in dichloromethane, washed with aqueous NaHCO₃ and the organiclayer was dried over Na₂SO₄, and concentrated.

Example 175D ethyl2-(1H-indol-4-yloxy)-4-(4-(1-(4′-chlorobiphenyl-2-yl)ethyl)piperazin-1-yl)benzoate

EXAMPLE 175C (193 mg) and ethyl 2-(1H-indol-4-yloxy)-4-fluorobenzoate(211 mg) in dimethysulfoxide (15 mL) was treated with potassium hydrogenphosphate (168 mg) at 135° C. overnight and cooled. The reaction mixturewas diluted with dichloromethane and washed with water. The organiclayer was concentrated. The concentrate was dissolved indichloromethane, loaded onto a silica gel column, eluted with 0%-10% 10M ammonia methanol in dichloromethane.

Example 175E2-(1H-indol-4-yloxy)-4-(4-(1-(4′-chlorobiphenyl-2-yl)ethyl)piperazin-1-yl)benzoicacid

EXAMPLE 175D (200 mg) in tetrahydrofuran (10 mL) and methanol (10 mL)was treated with 10% NaOH (3 mL) at 50° C. overnight and neutralizedwith HCl. The mixture was concentrated and the concentrate was taken upin water and extracted with dichloromethane. The organic layer was driedover Na₂SO₄ and concentrated.

Example 175F4-(4-(1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide

To a mixture of EXAMPLE 175E (66 mg),3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide (75mg) and 4-dimethylaminopyridine (58.4 mg) in dichloromethane (5 mL) wasadded 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride(45.8 mg). The mixture was stirred at ambient temperature overnight andconcentrated. The concentrate was purified by RP HPLC (10-70%acetonitrile in 0.1% trifluoroacetic acid water/70 minutes). The desiredfractions were concentrated to remove acetonitrile and the concentratewas diluted with dichloromethane and neutralized with aqueous NaHCO₃.The dichloromethane layer was dried over Na₂SO₄ and concentrated toprovide the title compound. ¹H NMR (500 MHz, dimethysulfoxide-d₆) δ ppm11.31 (1H, s), 11.25 (1H, s), 8.62 (1H, t), 8.50 (1H, d), 7.68 (1H, dd),7.53 (2H, d), 7.46 (2H, d), 7.37 (1H, t), 7.24-7.31 (4H, m), 7.17 (1H,d), 7.12 (1H, dd), 7.07 (1H, d), 6.96 (1H, t), 6.69 (1H, dd), 6.42 (1H,d), 6.26 (2H, s), 3.85 (2H, dd), 3.21-3.33 (5H, m), 3.01 (4H, s),2.29-2.39 (2H, m), 2.15-2.22 (2H, m), 1.83-1.94 (1H, m), 1.57-1.68 (2H,m), 1.22-1.31 (2H, m), 1.17 (3H, d).

Example 176N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamideExample 176A4-((4-aminotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamide

A mixture of 4-chloro-3-nitrobenzenesulfonamide,4-(aminomethyl)tetrahydro-2H-pyran-4-amine bis-hydrochloric acid saltand triethylamine in dioxane (10 mL) was heated at 110° C. overnight.After cooling, the reaction mixture was diluted with water (10 mL), andthe solid was filtered to give the title compound.

Example 176BN-((4-(((4-aminotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 55B for EXAMPLE 1F andEXAMPLE 176A(4-aminotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamide)for EXAMPLE 1G in EXAMPLE 1H. ¹H NMR (500 MHz, dimethysulfoxide-d₆) δ11.15 (s, 1H), 8.51 (s, 1H), 8.45 (d, J=2.14 Hz, 1H), 7.70 (dd, J=9.0,1.98 Hz, 1H), 7.59 (d, J=8.85 Hz, 1H), 7.34 (d, J=8.24 Hz, 2H), 7.22 (t,J=2.59 Hz, 1H), 7.11-7.12 (m, 2H), 7.04 (d, J=8.54 Hz, 2H), 6.93 (t,J=7.78 Hz, 1H), 6.62 (dd, J=9.0, 1.98 Hz, 1H), 6.34 (d, J=7.63 Hz, 1H),6.20-6.23 (m, 2H), 3.55-3.70 (m, 6H), 2.96 (m, 3H), 2.71 (s, 2H), 2.16(m, 6H), 1.95 (m, 2H), 1.70-1.74 (m, 2H), 1.55-1.59 (m, 2H), 1.37-1.39(m, 2H), 0.92 (s, 6H).

Example 1774-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

A mixture of EXAMPLE 26C (2.85 g, 10 mmol), EXAMPLE 1F (1.577 g, 5mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride(1.917 g, 10 mmol), 4-(dimethylamino)pyridine (1.222 g, 10 mmol), andtriethyl amine (2.8 mL, 20 mmol) was treated with CH₂Cl₂ (20 mL) andN,N-dimethylformamide (2 mL). The reaction mixture was stirred overnight. The solvent was removed, and the residue was partitioned betweenwater and ethyl acetate. The organic layers were washed with 1% HCltwice, then with sat NaHCO₃, brine, dried, filtered, and concentratedThe residue was purified by reverse phase HPLC on a C18 column using agradient of 40-60% acetonitrile/0.1% TFA in water to give the titlecompound as the trifluoroacetate salt. The TFA salt was dissolved indichloromethane (6 ml) and washed with 50% aqueous NaHCO₃. The organiclayer was dried over anhydrous Na₂SO₄ and concentrated to give the titlecompound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.18 (s, 2H),8.59-8.64 (m, 2H), 7.80 (dd, 1H), 7.52 (d, 1H), 7.39-7.42 (m, 2H), 7.33(d, 2H), 7.16 (d, 1H), 7.10 (d, 1H), 7.03 (d, 2H), 6.8 (dd, 1H), 6.65(dd, 1H), 6.40 (s, 1H), 6.14 (d, 1H), 3.85 (dd, 2H), 3.24-3.32 (m, 4H),3.03 (s, 3H), 2.73 (s, 2H), 2.12-2.17 (m, 5H), 1.68-1.94 (m, 3H), 1.61(d, 2H), 1.37 (t, 2H), 1.24-1.27 (m, 2H), 0.92 (s, 6H).

Example 178Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 178ATrans-4-(4-morpholinocyclohexylamino)-3-nitrobenzenesulfonamide

This EXAMPLE was prepared by substituting4-amino-N-morpholinylpiperidine for 1-(tetrahydropyran-4-yl)methylaminein EXAMPLE 1F.

Example 178B

Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as in EXAMPLE 177 by replacing EXAMPLE1F with EXAMPLE 178A. ¹H NMR (500 MHz, pyridine-d₅) δ 12.29 (s, 1H),9.29 (d, J=2.1 Hz, 1H), 8.37 (d, J=7.6 Hz, 1H), 8.32 (dd, J=9.3, 2.3 Hz,1H), 8.18 (d, J=8.8 Hz, 1H), 7.52-7.57 (m, 2H), 7.39-7.47 (m, 3H), 7.10(dd, J=8.7, 2.3 Hz, 1H), 7.05-7.08 (m, 2H), 6.90 (d, J=9.5 Hz, 1H), 6.74(dd, J=9.0, 2.3 Hz, 1H), 6.59-6.63 (m, 1H), 6.55 (d, J=2.4 Hz, 1H),3.72-3.78 (m, 4H), 3.33-3.43 (m, 1H), 2.99-3.09 (m, 4H), 2.76 (s, 2H),2.46-2.54 (m, 4H), 2.16-2.29 (m, 3H), 2.09-2.14 (m, 4H), 2.05 (d, J=11.9Hz, 2H), 1.97 (d, J=1.8 Hz, 2H), 1.87 (d, J=11.6 Hz, 2H), 1.19-1.42 (m,6H), 0.93 (s, 6H).

Example 1794-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 179A 4-(2-methoxyethylamino)-3-nitrobenzenesulfonamide

This EXAMPLE was prepared by substituting 2-methoxyethylamine for1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 179B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as in EXAMPLE 177 by replacing EXAMPLE1F with EXAMPLE 179A. ¹H NMR (400 MHz, DMSO-d₆) δ 11.20 (br. s, 1H)11.15 (s, 1H) 8.59 (m, 2H) 7.81 (dd, 1H) 7.50 (d, 1H) 7.36 (m, 4H) 7.08(m, 4H) 6.85 (dd, 1H) 6.65 (dd, 1H) 6.38 (m, 1H) 6.14 (m, 1H) 3.58 (m,4H) 3.30 (s, 3H) 3.03 (m, 4H) 2.73 (s, 2H) 2.15 (m, 6H) 1.96 (s, 2H)1.38 (t, 2H) 0.92 (s, 6H).

Example 1804-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamideExample 180A

(R)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzenesulfonamideand(S)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzenesulfonamide

This EXAMPLE was prepared by substituting(tetrahydro-2H-pyran-3-yl)methanamine for1-(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 180B(S)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzenesulfonamide

The racemic mixture of EXAMPLE 180A was resolved by chiral SFC on an ADcolumn (21 mm i.d.×250 mm in length) using a gradient of 10-30% 0.1%diethylamine methanol in CO₂ over 15 min (oven temperature: 40° C.; flowrate: 40 mL/min) to provide the title compound.

Example 180C(R)-3-nitro-4-((tetrahydro-2H-pyran-3-yl)methylamino)benzenesulfonamide

The racemic mixture of EXAMPLE 180A was resolved by chiral SFC on an ADcolumn (21 mm i.d.×250 mm in length) using a gradient of 10-30% 0.1%diethylamine methanol in CO₂ over 15 min (oven temperature: 40° C.; flowrate: 40 mL/min) to provide the title compound.

Example 180D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide

The title compound was prepared as in EXAMPLE 177 by replacing EXAMPLE1F with EXAMPLE 180B. ¹H NMR (400 MHz, DMSO-d₆) δ 11.17 (s, 2H),8.53-8.65 (m, 2H), 7.80 (d, 1H), 7.51 (d, 1H), 7.38-7.44 (m, 2H), 7.33(d, 2H), 7.15 (s, 1H), 7.02-7.09 (m, 3H), 6.82-6.92 (m, 1H), 6.65 (d,1H), 6.39 (s, 1H), 6.14 (s, 1H), 3.68-3.82 (m, 2H), 3.22-3.32 (m, 2H),3.13-3.22 (m, 1H), 3.03 (s, 4H), 2.72 (s, 2H), 2.09-2.23 (m, 6H),1.78-1.98 (m, 4H), 1.56-1.66 (m, 1H), 1.43-1.51 (m, 1H), 1.37 (t, 2H),1.22-1.33 (m, 1H), 0.92 (s, 6H).

Example 1814-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide

The title compound was prepared as in EXAMPLE 177 by replacing EXAMPLE1F with EXAMPLE 180C. ¹H NMR (400 MHz, DMSO-d₆) δ 11.17 (s, 2H),8.53-8.65 (m, 2H), 7.80 (d, 1H), 7.51 (d, 1H), 7.38-7.44 (m, 2H), 7.33(d, 2H), 7.15 (s, 1H), 7.02-7.09 (m, 3H), 6.82-6.92 (m, 1H), 6.65 (d,1H), 6.39 (s, 1H), 6.14 (s, 1H), 3.68-3.82 (m, 2H), 3.22-3.32 (m, 2H),3.13-3.22 (m, 1H), 3.03 (s, 4H), 2.72 (s, 2H), 2.09-2.23 (m, 6H),1.78-1.98 (m, 4H), 1.56-1.66 (m, 1H), 1.43-1.51 (m, 1H), 1.37 (t, 2H),1.22-1.33 (m, 1H), 0.92 (s, 6H).

Example 1824-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as in EXAMPLE 177 by replacing EXAMPLE26C with EXAMPLE 150C. ¹H NMR (400 MHz, DMSO-d₆) δ 11.20 (br s, 1H),11.17 (s, 1H), 8.63 (t, 1H), 8.59 (d, 1H), 7.79 (dd, 1H), 7.51 (d, 1H),7.36 (m, 3H), 7.13 (m, 2H), 6.86 (dd, 1H), 6.66 (dd, 1H), 6.39 (s, 1H),6.15 (d, 1H), 4.10 (s, 2H), 3.85 (m, 3H), 3.50 (m, 2H), 3.42 (m, 2H),3.24 (m, 4H), 3.02 (m, 4H), 2.82 (m, 2H), 2.16 (m, 2H), 1.61 (m, 3H),1.25 (m, 4H), 1.17 (s, 6H).

Example 1834-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamideExample 183A4-((4-hydroxy-1-methylpiperidin-4-yl)methylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting4-(aminomethyl)-1-methylpiperidin-4-ol for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 183B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 183A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.04 (s, 1H),8.46-8.48 (m, 2H), 7.92 (s, 1H), 7.74 (d, 1H), 7.54 (d, 1H), 7.32-7.34(m, 5H), 6.97-7.05 (m, 5H), 6.74-6.76 (m, 1H), 6.55-6.57 (m, 1H), 6.33(s, 1H), 6.13 (d, 1H), 5.10 (s, 1H), 3.14-3.17 (m, 2H), 2.95 (br, 5H),2.71 (br, 2H), 2.14-2.17 (m, 6H), 1.95 (br s, 2H), 1.70 (br, 4H),1.36-1.39 (m, 2H), 1.24-1.26 (m, 2H), 0.92 (s, 6H).

Example 1844-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-3-fluoro-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 184A ethyl 2-(1H-indol-5-yloxy)-3,4-difluorobenzoate

This example was prepared by substituting ethyl 2,3,4-trifluorobenzoatefor ethyl 2,4-difluorobenzoate and 5-hydroxyindole for 5-hydroxyindazolein EXAMPLE 20A.

Example 184B ethyl2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-3-fluorobenzoate

This example was prepared by substituting EXAMPLE 184A for EXAMPLE 20Ain EXAMPLE 20D.

Example 184C2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-3-fluorobenzoicacid

This example was prepared by substituting EXAMPLE 184B for EXAMPLE 1D inEXAMPLE 1E.

Example 184D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-3-fluoro-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 184C for EXAMPLE 1Eand EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 10.98 (br s, 1H), 8.35 (d, 1H), 7.98 (dd, 1H),7.59 (dd, 1H), 7.35 (m, 3H), 7.28 (t, 1H), 7.21 (d, 1H), 7.06 (d, 2H),6.78 (m, 2H), 6.67 (m, 2H), 6.22 (s, 1H), 3.74 (dd, 2H), 3.39 (m, 4H),3.06 (m, 3H), 2.97 (m, 4H), 2.79 (m, 2H), 2.73 (s, 3H), 2.29 (m, 2H),2.18 (m, 2H), 2.05 (m, 2H), 1.81 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

Example 1854-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-3-fluoro-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 184C for EXAMPLE 1Eand EXAMPLE 173C for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 10.98 (br s, 1H), 8.33 (d, 1H), 8.02 (dd, 1H),7.50 (dd, 1H), 7.35 (m, 3H), 7.26 (t, 1H), 7.19 (d, 1H), 7.06 (d, 2H),6.77 (dd, 2H), 6.67 (m, 2H), 6.22 (s, 1H), 3.90 (dd, 2H), 3.57 (m, 5H),3.30 (dd, 2H), 3.06 (m, 3H), 2.94 (m, 4H), 2.78 (m, 2H), 2.27 (m, 4H),2.18 (m, 2H), 1.98 (m, 4H), 1.80 (m, 2H), 1.55 (m, 2H), 1.41 (t, 2H),0.94 (s, 6H).

Example 1864-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 183A for EXAMPLE 1Fand EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.12 (s, 1H), 8.49 (s, 1H), 8.42 (s, 1H),7.73-7.75 (m, 1H), 7.58 (d, 1H), 7.34 (d, 2H), 7.22 (s, 1H), 7.09 (d,1H), 7.01-7.05 (m, 3H), 6.92 (t, 1H), 6.61-6.62 (m, 1H), 6.31 (d, 1H),6.23 (s, 1H), 6.20 (s, 1H), 5.16 (s, 1H), 4.05 (s, 3H), 2.95 (br s, 6H),2.71 (br s, 2H), 2.62 (br, 3H), 2.16 (br s, 6H), 1.95 (br s, 2H), 1.72(br, 4H), 1.37-1.39 (m, 2H), 0.92 (s, 6H).

Example 187N-[(4-{[(3S,4R)-1-benzyl-3-hydroxypiperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamideExample 187A2-(1H-indol-5-yloxy)-N-(4-chloro-3-nitrophenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide

This example was prepared by substituting4-chloro-3-nitrobenzenesulfonamide for EXAMPLE 1F and EXAMPLE 26C forEXAMPLE 1E in EXAMPLE 1G.

Example 187BN-[(4-{[(3S,4R)-1-benzyl-3-hydroxypiperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide

A mixture of EXAMPLE 187A (0.158 g),(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid (0.049 g), andtriethylamine (0.1 mL) in dioxane (2 mL) was heated at 100° C.overnight. The solvent was removed, and the residue was re-dissolved in1:1 methanol:dimethylsulfoxide (3 mL). It was then purified by reversephase Prep HPLC. The residue was purified by reverse phase HPLC on a C18column using a gradient of 20-80% acetonitrile/0.1% TFA in water. Thedesired fractions were collected, and the organic solvent was partiallyremoved under reduced pressure. The resulting mixture was treated withsaturated aqueous NaHCO₃ mixture. It was then extracted with ethylacetate three times. The combined organic layers were washed with brine,dried (MgSO₄), filtered, and concentrated to give the desired product.¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.14 (s, 1H), 8.69 (d, 1H),8.14 (d, 1H), 7.77 (dd, 1H), 7.51 (d, 1H), 7.29-7.41 (m, 9H), 7.10-7.13(m, 1H), 7.13 (d, 2H), 6.84 (dd, 1H), 6.63 (dd, 1H), 6.38 (s, 1H), 6.13(d, 1H), 5.21-5.22 (br s, 1H), 3.82 (m, 2H), 3.62 (br s, 2H), 3.01 (brs, 4H), 2.71-2.82 (m, 4H), 2.12-2.15 (m, 7H), 1.94 (br s, 2H), 1.81 (brs, 2H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).

Example 188N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting4-(aminomethyl)tetrahydro-2H-pyran-4-amine for(3S,4R)-4-amino-1-benzylpiperidin-3-ol hydrochloric acid in EXAMPLE187B. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.08 (s, 1H), 8.60 (brs, 1H), 8.51 (d, 1H), 7.80 (dd, 1H), 7.54 (d, 1H), 7.32-7.36 (m, 4H),7.12 (d, 1H), 7.03-7.05 (m, 3H), 6.77 (dd, 1H), 6.58 (dd, 1H), 6.35 (s,1H), 6.13 (d, 1H), 3.61-3.70 (m, 4H), 3.53 (br s, 2H), 2.97 (br, 4H),2.71 (br, 2H), 2.16 (br s, 6H), 1.94 (br s, 2H), 1.67-1.72 (m, 2H),1.52-1.57 (m, 2H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).

Example 1894-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamideExample 189A4-[1-(2-methoxy-ethyl)-piperidin-4-ylamino]-3-nitro-benzenesulfonamide

1-(2-Methoxy-ethyl)-piperidin-4-ylamine (2.01 g) and triethylamine (3.24mL, 2.35 g) were added to 1,4-dioxane (60 mL).4-Chloro-3-nitrobenzenesulfonamide (2.50 g) was added, and the mixturewas heated to 90° C. for 16 hours. The mixture was cooled and thematerial purified by flash column chromatography on silica gel using 10%methanol in dichloromethane.

Example 189B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 189A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.12 (br s, 1H), 8.52 (d, 1H), 8.18 (d, 1H),7.76 (dd, 1H), 7.51 (d, 1H), 7.39-7.31 (m, 4H), 7.08-7.05 (m, 4H), 6.80(dd, 1H), 6.61, (dd, 1H), 6.36 (t, 1H), 6.14 (d, 1H), 3.70 (m, 1H), 3.50(t, 2H), 3.27 (s, 3H), 2.99 (m, 6H), 2.71 (br s, 4H), 2.16 (m, 6H),2.02-1.90 (m, 6H), 1.65 (m, 2H), 1.37 (t, 2H), 0.92 (s, 6H).

Example 1904-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 174A for EXAMPLE 1Fand EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.21 (br s, 1H), 9.14 (s, 1H), 8.45 (d, 1H),7.71 (dd, 1H), 7.52 (m, 2H), 7.34 (m, 2H), 7.26 (m, 1H), 7.15 (d, 1H),7.04 (m, 2H), 6.95 (t, 1H), 6.67 (m, 1H), 6.38 (d, 1H), 6.25 (m, 2H),3.01 (m, 4H), 2.87 (m, 5H), 2.72 (m, 2H), 2.33 (m, 4H), 2.15 (m, 6H),1.95 (s, 2H), 1.39 (m, 2H), 0.92 (s, 6H).

Example 1914-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamideExample 191A tert-butyl4-(4-(N-(2-(1H-indol-4-yloxy)-4-(-4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoyl)sulfamoyl)-2-nitrophenylamino)piperidine-1-carboxylate

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 1E andEXAMPLE 157A for EXAMPLE 1F in EXAMPLE 1G, except 5-7% methanol inCH₂Cl₂ was used for the chromatography.

Example 191B2-(1H-indol-4-yloxy)-N-(4-(1-(2-(tert-butyldimethylsilyloxy)ethyl)piperidin-4-ylamino)-3-nitrophenylsulfonyl)-4-(-4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide

EXAMPLE 191A (400 mg) was dissolved in CH₂Cl₂ (2.5 mL) and 4N HCl indioxane (2.5 mL), then stirred at room temperature for 30 minutes. Thereaction was concentrated and then partitioned between CH₂Cl₂ andsaturated aqueous NaHCO₃. The organic layer was washed with brine anddried over Na₂SO₄. After filtration and concentration the resultantcrude amine was slurried in CH₂Cl₂ (2.5 mL) and(tert-butyldimethylsilyloxy)acetaldehyde (73 mg) was added. Afterstirring for 15 minutes, sodium triacetoxyborohydride (400 mg) was addedand the reaction was stirred at room temperature overnight. The reactionwas diluted with CH₂Cl₂ and washed with saturated aqueous NaHCO₃ Theorganic layer was washed with brine and dried over Na₂SO₄. The productwas purified using column chromatography using 1.0-2.5% methanol inCH₂Cl₂

Example 191C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide

EXAMPLE 191B (46 mg) was dissolved in tetrahydrofuran (0.8 mL), then1.0M tetrabutyl ammonium fluoride in 95/5 tetrahydrofuran/H₂O (0.075 mL)was added and the reaction stirred at room temperature overnight. Thereaction was concentrated and purified with column chromatography using2-6% methanol in CH₂Cl₂. 1H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.15(br s, 1H), 8.44 (d, 1H), 8.13 (br d, 1H), 7.74 (dd, 1H), 7.55 (d, 1H),7.33 (d, 2H), 7.23 (s, 1H), 7.11 (d, 1H), 7.03 (m, 3H), 6.93 (dd, 1H),6.64 (d, 1H), 6.33 (d, 1H), 6.23 (s, 1H), 6.22 (s, 1H), 3.75 (br s, 1H),3.61 (br s, 2H), 3.40 (br s, 2H), 3.10 (br s, 2H), 2.98 br s, 4H), 2.78(br s, 2H), 2.71 (s, 2H), 2.16 (br m, 6H), 2.00 (br d, 2H), 1.95 (s,2H), 1.72 (br s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 1944-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 1E andEXAMPLE 189A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.19 (br s, 1H), 8.46 (d, 1H), 8.17 (d, 1H),7.72 (dd, 1H), 7.55 (d, 1H), 7.35 (d, 2H), 7.25 (t, 1H), 7.12 (d, 1H),7.07-7.02 (m, 3H), 6.94 (t, 1H), 6.66, (dd, 1H), 6.36 (d, 1H), 6.24 (m,2H), 3.73 (m, 1H), 3.52 (t, 2H), 3.27 (s, 3H), 3.00 (m, 6H), 2.79 (m,2H), 2.72 (br s, 2H), 2.16 (m, 6H), 2.04-1.93 (m, 6H), 1.68 (m, 2H),1.37 (t, 2H), 0.92 (s, 6H).

Example 1954-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamideExample 195A4-(1-(3-(tert-butyldimethylsilyloxy)propyl)piperidin-4-ylamino)-3-nitrobenzenesulfonamide

A mixture of EXAMPLE 157B (300 mg),(3-bromopropoxy)(tert-butyl)dimethylsilane (304 mg) and cesium carbonate(967 mg) was suspended in anhydrous N,N-dimethylformamide (5 mL). Thereaction mixture was heated at 70° C. overnight. The reaction mixturewas cooled to room temperature and diluted with ethyl acetate. Theorganic phase was washed with water, brine, dried over anhydrous sodiumsulfate, and concentrated. The crude material was purified using flashcolumn purification with 3-10% methanol/dichloromethane to afford thetitle compound.

Example 195B2-(1H-indol-4-yloxy)-N-(4-(1-(3-(tert-butyldimethylsilyloxy)propyl)piperidin-4-ylamino)-3-nitrophenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 1E andEXAMPLE 195A for EXAMPLE 1F in EXAMPLE 1G.

Example 195C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide

A mixture of EXAMPLE 195B (180 mg) in anhydrous tetrahydrofuran (1 mL)and tetrabutyl ammonium fluoride (0.5 mL IM in tetrahydrofuran) wasstirred at room temperature for 2 hours. The solvent was removed undervacuum. The residue was purified by reverse phase HPLC on a C18 columnusing a gradient of 40-70% acetonitrile/0.1% trifluoroacetic acid inwater to give the title compound as the trifluoroacetate salt. Thetrifluoroacetic acid salt was dissolved in dichloromethane (6 ml) andwashed with 50% aqueous NaHCO₃. The organic layer was dried overanhydrous Na₂SO₄, filtered, and concentrated to give the title compound.¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.16 (s, 1H), 8.43 (d, 1H),8.10 (m, 1H), 7.74 (dd, 1H), 7.57 (d, 1H), 7.34 (d, 2H), 7.23 (m, 1H),7.10 (m, 1H), 7.02 (m, 3H), 6.93 (m, 1H), 6.65 (dd, 1H), 6.34 (d, 1H),6.22 (m, 2H), 3.74 (m, 2H), 3.47 (m, 4H), 3.14 (m, 2H), 2.97 (m, 4H),2.74 (m, 4H), 2.60 (m, 1H), 2.17 (m, 4H), 1.97 (m, 4H), 1.69 (m, 4H),1.40 (m, 2H), 0.93 (s, 6H).

Example 1964-[4-({4′-chloro-3-[3-(dimethylamino)propyl]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 196A 4′-chloro-3-hydroxybiphenyl-2-carbaldehyde

The title compound was prepared as described in EXAMPLE 175A byreplacing 1-(2-bromophenyl)ethanone with 2-bromo-6-hydroxybenzaldehyde.

Example 196B tert-butyl4-((4′-chloro-3-hydroxybiphenyl-2-yl)methyl)piperazine-1-carboxylate

The title compound was prepared as described in EXAMPLE 1A by replacing4′-chlorobiphenyl-2-carboxaldehyde with EXAMPLE 196A.

Example 196C tert-butyl4-((4′-chloro-3-(trifluoromethylsulfonyloxy)biphenyl-2-yl)methyl)piperazine-1-carboxylate

To a mixture of EXAMPLE 196B (390 mg) in pyridine (5 ml) at 0° C. wasadded dropwise trifluoromethanesulfonic anhydride (0.326 ml). Thereaction mixture was stirred in an ice bath for 1 hour and diluted withethyl acetate. The resulting mixture was washed with brine extensivelyand the organic layer was dried over Na₂SO₄, filtered, and concentratedto provide the title compound.

Example 196D tert-butyl4-((4′-chloro-3-(3-(dimethylamino)prop-1-ynyl)biphenyl-2-yl)methyl)piperazine-1-carboxylate

To a mixture of EXAMPLE 196C (380 mg), N,N-dimethylprop-2-yn-1-amine(0.227 ml), tetrakis(triphenylphosphine)palladium(0) (123 mg) andtriethylamine (0.492) in N,N-dimethylformamide (1.5 ml) was addedcopper(I) iodide (27.1 mg) and ^(t)BuNI (394 mg). The reaction mixturewas heated at 100° C. for 4 hours, cooled and diluted with ethylacetate. The organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by flash chromatography, eluting with a mixture ofmethanol, dichloromethane and triethyl amine to provide the titlecompound.

Example 196E tert-butyl4-((4′-chloro-3-(3-(dimethylamino)propyl)biphenyl-2-yl)methyl)piperazine-1-carboxylate

EXAMPLE 196D (200 mg) in methanol (8 ml) was treated with platinum(IV)oxide (29.1 mg) under H₂ atmosphere overnight. The insoluble materialwas filtered off and the filtrate was concentrated to provide the titlecompound.

Example 196F3-(4′-chloro-2-(piperazin-1-ylmethyl)biphenyl-3-yl)-N,N-dimethylpropan-1-amine

The title compound was prepared as described in EXAMPLE 175C byreplacing EXAMPLE 175B with EXAMPLE 196E.

Example 196G ethyl2-(1H-indol-4-yloxy)-4-(4-((4′-chloro-3-(3-(dimethylamino)propyl)biphenyl-2-yl)methyl)piperazin-1-yl)benzoate

The title compound was prepared as described in EXAMPLE 175D byreplacing EXAMPLE 175C with EXAMPLE 196F.

Example 196H2-(1H-indol-4-yloxy)-4-(4-((4′-chloro-3-(3-(dimethylamino)propyl)biphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared as described in EXAMPLE 175E byreplacing EXAMPLE 175D with EXAMPLE 196G.

Example 196I4-[4-({4′-chloro-3-[3-(dimethylamino)propyl]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 175F byreplacing EXAMPLE 175E with EXAMPLE 196H. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.11 (s, 1H), 8.38-8.44 (m, 2H), 7.68 (dd, 1H),7.56 (d, 1H), 7.44 (d, 2H), 7.19-7.29 (m, 5H), 7.07 (d, 1H), 6.99 (dd,1H), 6.87-6.93 (m, 2H), 6.59 (dd, 1H), 6.26 (d, 1H), 6.23 (s, 1H), 6.19(d, 1H), 3.84 (dd, 2H), 3.22-3.29 (m, 4H), 2.87 (s, 6H), 2.69-2.75 (m,2H), 2.59 (s, 5H), 2.14 (s, 4H), 1.83-1.92 (m, 3H), 1.56-1.65 (m, 2H),1.19-1.31 (m, 4H), 0.81-0.90 (m, 1H)

Example 1974-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamideExample 197A2-(1H-indol-5-yloxy)-N-(4-(1-(3-(tert-butyldimethylsilyloxy)propyl)piperidin-4-ylamino)-3-nitrophenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 195A for EXAMPLE 1F in EXAMPLE 1G.

Example 197B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 197A for EXAMPLE 195Bin EXAMPLE 195C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.07 (bs,1H), 8.50 (d, 1H), 8.14 (d, 1H), 7.75 (dd, 1H), 7.52 (d, 1H), 7.34 (m,4H), 7.02 (m, 4H), 6.78 (dd, 1H), 6.59 (dd, 1H), 6.34 (m, 1H), 6.14 (d,1H), 3.46 (m, 4H), 3.16 (m, 2H), 2.98 (m, 4H), 2.68 (m, 4H), 2.60 (m,1H), 2.16 (m, 6H), 1.97 (m, 4H), 1.68 (m, 4H), 1.38 (t, 2H), 0.93 (s,6H).

Example 1984-{4-[(4′-chloro-4-morpholin-4-yl-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 198A tert-butyl4-((4′-chloro-4-hydroxybiphenyl-2-yl)methyl)piperazine-1-carboxylate

This example was prepared by substituting EXAMPLE 125A for4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.

Example 198B tert-butyl4-((4′-chloro-4-(trifluoromethylsulfonyloxy)biphenyl-2-yl)methyl)piperazine-1-carboxylate

A mixture of EXAMPLE 198A (3.0 g), trifluoromethanesulfonic anhydride(3.14 g) in anhydrous pyridine (50 mL) mixture was stirred at roomtemperature overnight. The reaction mixture was diluted with ethylacetate. The organic phase was washed with water, brine, dried overanhydrous sodium sulfate and concentrated. The residue was used in thenext step without further purification.

Example 198C tert-butyl4-((4′-chloro-4-morpholinobiphenyl-2-yl)methyl)piperazine-1-carboxylate

A suspension of EXAMPLE 198B (500 mg), morpholine (80 mg), palladium(II) acetate (22 mg), biphenyl-2-yldi-tert-butylphosphine (50 mg) andcesium carbonate (427 mg) in anhydrous tetrahydrofuran (6 mL) was heatedat 50° C. overnight. The reaction mixture was cooled to room temperatureand diluted with ethyl acetate. The organic phase was washed with water,brine, dried over anhydrous sodium sulfate, filtered and concentrated.The crude material was purified by flash column purification with 30-50%ethyl acetate/hexane to afford the title compound.

Example 198D4-(4′-chloro-2-(piperazin-1-ylmethyl)biphenyl-4-yl)morpholine

This example was prepared by substituting EXAMPLE 198C for EXAMPLE 1A inEXAMPLE 1B.

Example 198E methyl2-(1H-indol-4-yloxy)-4-(4-((4′-chloro-4-morpholinobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 24F for EXAMPLE 20Aand EXAMPLE 198D for EXAMPLE 20C in EXAMPLE 20D.

Example 198F2-(1H-indol-4-yloxy)-4-(4-((4′-chloro-4-morpholinobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 198E for EXAMPLE 1D inEXAMPLE 1E.

Example 198G4-{4-[(4′-chloro-4-morpholin-4-yl-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 198F for EXAMPLE 26Cin EXAMPLE 177. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.26 (bs, 1H),8.63 (t, 1H), 8.49 (d, 1H), 7.66 (dd, 1H), 7.54 (d, 1H), 7.40 (m, 4H),7.29 (m, 1H), 7.02 (m, 6H), 6.73 (dd, 1H), 6.39 (d, 1H), 6.30 (m, 2H),3.85 (dd, 2H), 3.74 (m, 4H), 3.24 (m, 6H), 3.10 (m, 8H), 2.29 (m, 4H),1.89 (m, 1H), 1.63 (m, 2H), 1.28 (m, 2H).

Example 1994-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamideExample 199A tert-butyl4-((4′-chloro-3-hydroxybiphenyl-2-yl)methyl)piperazine-1-carboxylate

The title compound was prepared as described in EXAMPLE 1A by replacingEXAMPLE 27C with EXAMPLE 196A.

Example 199B tert-butyl4-((4′-chloro-3-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazine-1-carboxylate

To a mixture of EXAMPLE 199A (1.5 g) in N,N-dimethylformamide (20 ml)was added 60% sodium hydride (0.596 g). The mixture was stirred at roomtemperature for 30 minutes and dimethylaminoethyl chloride hydrochloridesalt (1.073 g) was added. After the resulting mixture was stirredovernight, additional 60% sodium hydride (0.596 g) anddimethylaminoethyl chloride hydrochloride salt (1.073 g) were added. Thereaction mixture was further stirred overnight, diluted with ethylacetate and washed with water, saturated NaHCO₃ and brine. The organiclayer was dried over Na₂SO₄, filtered, and concentrated to provide thetitle compound.

Example 199C2-(4′-chloro-2-(piperazin-1-ylmethyl)biphenyl-3-yloxy)-N,N-dimethylethanamine

To a mixture of EXAMPLE 199B (2 g) in dichloromethane (10 ml) was addedtrifluoroacetic acid (10 ml) at 0° C. The reaction mixture was stirredat room temperature for 30 minutes and concentrated. The residue wasloaded onto a C18 column, and eluted with 0-50% 0.1% trifluoroaceticacid/water in acetonitrile. The title compound was obtained as atrifluoroacetic acid salt.

Example 199D ethyl2-(1H-indol-4-yloxy)-4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)benzoate

The title compound was prepared as described in EXAMPLE 175D byreplacing EXAMPLE 175C with EXAMPLE 199C.

Example 199E2-(1H-indol-4-yloxy)-4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)biphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared as described in EXAMPLE 175E byreplacing EXAMPLE 175D with EXAMPLE 199D.

Example 199F4-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 175F byreplacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 199E and EXAMPLE173C, respectively. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.13 (s,1H), 8.41 (d, 1H), 8.12 (d, 1H), 7.70 (dd, 1H), 7.58 (d, 1H), 7.52 (d,2H), 7.43 (d, 2H), 7.31 (t, 1H), 7.22 (t, 1H), 7.06 (dd, 2H), 6.89-6.97(m, 2H), 6.84 (d, 1H), 6.64 (dd, 1H), 6.30 (d, 1H), 6.24 (dd, 2H), 4.14(t, 2H), 3.90 (dd, 2H), 3.53-3.73 (m, 2H), 3.22-3.32 (m, 4H), 2.93 (s,6H), 2.34-2.46 (m, 7H), 2.29 (s, 5H), 1.97 (d, 2H), 1.73 (d, 2H),1.41-1.62 (m, 4H).

Example 2014-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamideExample 201A4-(4-(diethylamino)cyclohexylamino)-3-nitrobenzenesulfonamide

This example was prepared by substitutingN¹,N¹-diethylcyclohexane-1,4-diamine for1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A.

Example 201B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 201A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz, pyridine-ds)δ ppm 12.28 (s, 1H), 9.29 (d, 1H), 8.29-8.38 (m, 2H), 8.19 (d, 1H),7.52-7.57 (m, 2H), 7.40-7.47 (m, 3H), 7.10 (dd, 1H), 7.06 (d, 2H), 6.92(d, 1H), 6.74 (dd, 1H), 6.61 (s, 1H), 6.55 (d, 1H), 3.31-3.42 (m, 1H),3.00-3.08 (m, 4H), 2.76 (s, 2H), 2.54-2.61 (m, 1H), 2.51 (q, 4H),2.21-2.28 (m, 2H), 2.08-2.15 (m, 4H), 2.04 (d, 2H), 1.97 (s, 2H), 1.81(d, 2H), 1.38 (t, 2H), 1.29-1.36 (m, 2H), 1.17-1.28 (m, 2H), 1.05 (t,6H), 0.93 (s, 6H).

Example 2024-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dimethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamideExample 202A4-(4-(dimethylamino)cyclohexylamino)-3-nitrobenzenesulfonamide

This example was prepared by substitutingN¹,N¹-dimethylcyclohexane-1,4-diamine for1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A.

Example 202B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dimethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 1E andEXAMPLE 202A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz, pyridine-d₅)δ ppm 12.45 (s, 1H), 9.21 (d, 1H), 8.33 (d, 1H), 8.27 (dd, 1H), 8.18 (d,1H), 7.48 (t, 1H), 7.45 (d, 2H), 7.40 (d, 1H), 7.11 (t, 1H), 7.08 (d,2H), 6.87 (d, 1H), 6.72-6.81 (m, 3H), 6.67 (d, 1H), 3.31-3.41 (m, 1H),3.00-3.06 (m, 4H), 2.77 (s, 2H), 2.31 (s, 6H), 2.25 (t, 2H), 2.20-2.25(m, 1H), 2.10-2.16 (m, 4H), 2.00-2.07 (d, 2H), 1.97 (s, 2H), 1.88 (d,2H), 1.39 (t, 3H), 1.34 (d, 2H), 1.15-1.28 (m, 4H), 0.94 (s, 6H).

Example 2034-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 1E andEXAMPLE 201A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz, pyridine-ds)δ 12.44 (s, 1H), 9.21 (d, 1H), 8.34 (d, 1H), 8.28 (dd, 1H), 8.18 (d,1H), 7.47-7.50 (m, 1H), 7.45 (d, 2H), 7.40 (d, 1H), 7.11 (t, 1H), 7.08(d, 2H), 6.90 (d, 1H), 6.73-6.81 (m, 3H), 6.67 (d, 1H), 3.32-3.40 (m,1H), 2.99-3.06 (m, 4H), 2.76 (s, 2H), 2.52-2.60 (m, 1H), 2.49 (q, 4H),2.25 (t, 2H), 2.09-2.16 (m, 4H), 2.04 (d, 2H), 1.97 (s, 2H), 1.79 (d,2H), 1.29-1.42 (m, 4H), 1.16-1.28 (m, 2H), 1.04 (t, 6H), 0.92-0.95 (m,6H).

Example 204Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 204Atrans-4-(4-morpholinocyclohexylamino)-3-nitrobenzenesulfonamide

This example was prepared by substitutingtrans-4-morpholinocyclohexanamine for1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A.

Example 204Btrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 1E andEXAMPLE 204A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz, pyridine-ds)δ 12.45 (s, 1H), 9.21 (d, 1H), 8.36 (d, 1H), 8.26 (dd, 1H), 8.16 (d,1H), 7.47-7.51 (m, 1H), 7.45 (d, 1H), 7.40 (d, 1H), 7.12 (t, 1H), 6.87(d, 1H), 6.73-6.81 (m, 3H), 6.68 (d, 1H), 3.71-3.78 (m, 2H), 3.33-3.42(m, 1H), 3.00-3.06 (m, 4H), 2.76 (s, 2H), 2.44-2.52 (m, 4H), 2.25 (t,2H), 2.16-2.23 (m, 2H), 2.09-2.16 (m, 4H), 2.06 (d, 2H), 1.97 (s, 2H),1.86 (s, 2H), 1.39 (t, 2H), 1.17-1.35 (m, 6H), 0.94 (s, 6H).

Example 2054-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 177 by replacingEXAMPLE 26C and EXAMPLE 1F with EXAMPLE 199E and EXAMPLE 21A,respectively. ¹H NMR (500 MHz, dichloromethane-d₂) δ 8.70 (d, 1H), 8.56(s, 1H), 8.40 (d, 1H), 7.95 (dd, 1H), 7.91 (d, 1H), 7.46 (d, 2H),7.24-7.35 (m, 5H), 7.15 (t, 1H), 6.90 (dd, 2H), 6.83 (d, 1H), 6.75 (d,1H), 6.60 (dd, 1H), 6.41 (d, 1H), 6.19 (d, 1H), 4.05 (t, 2H), 3.58 (s,1H), 3.32 (s, 2H), 2.95-3.02 (m, 4H), 2.66-2.80 (m, 4H), 2.30-2.35 (m,4H), 2.24-2.29 (m, 9H), 2.15-2.23 (m, 2H), 2.05 (d, 2H), 1.63-1.73 (m,2H)

Example 2064-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 177 by replacingEXAMPLE 26C and EXAMPLE 1F with EXAMPLE 175E and EXAMPLE 21A,respectively. ¹H NMR (400 MHz, dichloromethane-d₂) δ 8.70 (d, 1H), 8.51(s, 1H), 8.40 (d, 1H), 7.94 (dd, 1H), 7.90 (d, 1H), 7.54 (d, 1H), 7.33(t, 4H), 7.21-7.27 (m, 2H), 7.10-7.19 (m, 4H), 6.91 (d, 1H), 6.73 (d,1H), 6.55-6.60 (m, 1H), 6.41 (s, 1H), 6.16 (d, 1H), 3.52-3.63 (m, 1H),3.36 (q, 1H), 2.96-3.07 (m, 4H), 2.72-2.79 (m, 2H), 2.33-2.41 (m, 2H),2.27 (s, 3H), 2.14-2.27 (m, 4H), 2.00-2.09 (m, 2H), 1.63-1.74 (m, 2H),1.19 (d, 3H).

Example 2074-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(dimethylamino)tetrahydro-2H-pyran-4-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting4-(aminomethyl)-N,N-dimethyltetrahydro-2H-pyran-4-amine for(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in EXAMPLE187B. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 1H), 8.84 (brs, 1H), 8.59 (d, 1H), 7.84 (dd, 1H), 7.51 (d, 1H), 7.39-7.43 (m, 2H),7.33 (d, 2H), 7.17-7.21 (m, 2H), 7.03 (d, 2H), 6.89 (dd, Hz, 1H), 6.64(d, 1H), 6.40 (s, 1H), 6.13 (d, 1H), 3.72-3.75 (m, 2H), 3.34-3.57 (m,4H), 3.02 (br, 4H), 2.71 (br, 2H), 2.27 (s, 6H), 2.16 (br s, 6H), 1.94(br s, 2H), 1.78-1.85 (m, 2H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).

Example 208N-({4-[(2-aminocyclohexyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamideExample 208A

This example was prepared by substituting tert-butyl2-aminocyclohexylcarbamate for (3S,4R)-4-amino-1-benzylpiperidin-3-ol,hydrochloric acid in EXAMPLE 187B.

Example 208BN-({4-[(2-aminocyclohexyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide

EXAMPLE 208A (0.1 g) in dimethylsulfoxide (4 mL) was heated undermicrowave conditions (200° C., 1 hour). The residue was purified byreverse phase HPLC on a C18 column using a gradient of 30-70%acetonitrile/0.1% TFA in water. The desired fractions were collected,and the organic solvent was partially removed under reduced pressure.The resulting mixture was treated with saturated aqueous NaHCO₃ mixture.It was then extracted with ethyl acetate three times. The combinedorganic layers were washed with brine, dried (MgSO₄), filtered, andconcentrated to give the title compound. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.02 (s, 1H), 8.45 (s, 1H), 8.05 (d, 1H),7.79-7.81 (m, 1H), 7.56 (d, 1H), 7.30-7.34 (m, 4H), 6.98-7.06 (m, 4H),6.73 (d, 1H), 6.54 (dd, 1H), 6.33 (s, 1H), 6.11 (d, 1H), 3.64-3.70 (m,1H), 2.93 (br, 4H), 2.71 (br, 2H), 2.14-2.16 (br s, 6H), 1.95 (br s,2H), 1.67-1.73 (m, 2H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).

Example 2094-[4-({4′-chloro-4-[3-(dimethylamino)prop-1-ynyl]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 209A tert-butyl4-((4′-chloro-4-(3-(dimethylamino)prop-1-ynyl)biphenyl-2-yl)methyl)piperazine-1-carboxylate

A suspension of EXAMPLE 198B (800 mg), N,N-dimethylprop-2-yn-1-amine(373 mg), copper(I) iodide (57 mg),tetrakis(triphenylphosphine)palladium(0) (259 mg), triethylamine (757mg) and tert-butyl ammonium iodide (829 mg) in anhydrousN,N-dimethylformamide (5 mL) was heated at 100° C. for 5 hours. Thereaction mixture was cooled to room temperature and diluted with ethylacetate. The organic phase was washed with water, brine, dried overanhydrous sodium sulfate, filtered, and concentrated. The crude materialwas purified by flash column purification with 0-3%methanol/dichloromethane to afford the title compound.

Example 209B3-(4′-chloro-2-(piperazin-1-ylmethyl)biphenyl-4-yl)-N,N-dimethylprop-2-yn-1-amine

This example was prepared by substituting EXAMPLE 209A for EXAMPLE 1A inEXAMPLE 1B.

Example 209C methyl2-(1H-indol-4-yloxy)-4-(4-((4′-chloro-4-(3-(dimethylamino)prop-1-ynyl)biphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 24F for EXAMPLE 20Aand EXAMPLE 209B for EXAMPLE 20C in EXAMPLE 20D.

Example 209D2-(1H-indol-4-yloxy)-4-(4-((4′-chloro-4-(3-(dimethylamino)prop-1-ynyl)biphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 209C for EXAMPLE 1D inEXAMPLE 1E.

Example 209E4-[4-({4′-chloro-4-[3-(dimethylamino)prop-1-ynyl]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 209D for EXAMPLE 26Cin EXAMPLE 177. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.23 (bs, 1H),8.57 (t, 1H), 8.47 (d, 1H), 7.67 (dd, 1H), 7.54 (m, 2H), 7.43 (m, 5H),7.24 (m, 2H), 7.14 (m, 1H), 7.03 (m, 1H), 6.94 (m, 1H), 6.71 (d, 1H),6.38 (d, 1H), 6.27 (d, 2H), 3.85 (m, 2H), 3.60 (m, 2H), 3.23 (m, 6H),3.04 (m, 4H), 2.35 (s, 6H), 2.28 (m, 4H), 1.88 (m, 1H), 1.58 (m, 2H),1.24 (m, 2H).

Example 2104-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[1-(4,4,4-trifluorobutyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamideExample 210A3-nitro-4-(1-(4,4,4-trifluorobutyl)piperidin-4-ylamino)benzenesulfonamide

EXAMPLE 157B (600 mg) was combined with 1,1,1-trifluoro-4-iodobutane(595 mg) and potassium carbonate (829 mg) in acetonitrile (15 mL). Thereaction was heated to 70° C. overnight. The reaction was concentrated,and then taken up in ether and concentrated again. The product was usedin the next step without further purification.

Example 210B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[1-(4,4,4-trifluorobutyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 210A for EXAMPLE 1Fand EXAMPLE 55B for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.20 (s, 1H), 8.47 (d, 1H), 8.20 (d, 1H), 7.72(dd, 1H), 7.54 (d, 1H), 7.34 (d, 2H), 7.25 (t, 1H), 7.14 (d, 1H), 7.05(m, 3H), 6.95 (t, 1H), 6.68 (dd, 1H), 6.38 (d, 1H), 6.25 (s, 2H), 3.71(m, 1H), 3.01 (m, 4H), 2.92 (m, 2H), 2.72 (s, 2H), 2.40 (m, 2H), 2.30(m, 2H), 2.16 (m, 6H), 1.95 (m, 4H), 1.68 (m, 4H), 1.38 (t, 2H), 1.24(br s, 1H), 0.92 (s, 6H).

Example 2114-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[2-(4-hydroxy-1-methylpiperidin-4-yl)ethyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting4-(2-aminoethyl)-1-methylpiperidin-4-ol for(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in EXAMPLE187B. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.05 (s, 1H), 8.61 (s,1H), 8.47 (d, 1H), 7.77 (dd, 1H), 7.54 (d, 1H), 7.32-7.34 (m, 4H), 7.04(d, 2H), 7.01 (s, 1H), 6.90 (d, 2H), 6.76 (dd, 1H), 6.57 (dd, 1H), 6.33(s, 1H), 6.13 (d, 1H), 4.92 (s, 1H), 3.43-3.46 (m, 2H), 2.95-3.01 (br,8H), 2.71 (br, 2H), 2.65 (s, 3H), 2.12-2.16 (br s, 6H), 1.95 (br s, 2H),1.77-1.80 (m, 2H), 1.67-1.71 (m, 4H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).

Example 2124-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-2-yl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide

This example was prepared by substituting4-(2-aminoethyl)-1-methylpiperidin-4-ol for(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in EXAMPLE187B. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.16 (s, 1H), 8.58 (s,1H), 8.28 (d, 1H), 7.82 (dd, 1H), 7.51 (d, 1H), 7.39-7.42 (m, 2H), 7.33(d, 2H), 7.20 (d, 1H), 7.17 (d, 1H), 7.14 (d, 1H), 7.03 (d, 2H), 6.86(d, 1H), 6.85 (d, 1H), 6.65 (dd, 1H), 6.39 (s, 1H), 6.15 (d, 1H),3.87-3.90 (m, 2H), 3.20-3.24 (m, 2H), 3.04 (br, 4H), 2.73 (br, 2H),2.11-2.17 (m, 5H), 1.95 (br s, 2H), 1.71-1.75 (m, 2H), 1.36-1.39 (m,2H), 0.92 (s, 6H).

Example 2134-(4-{[4′-chloro-4-(2-hydroxyethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 213A4-(2-(tert-butyldimethylsilyloxy)ethoxy)-4′-chlorobiphenyl-2-carbaldehyde

A mixture of EXAMPLE 125A (0.5 g),(2-bromoethoxy)(tert-butyl)dimethylsilane (0.771 g) and cesium carbonate(1.4 g) was suspended in anhydrous N,N-dimethylformamide (5 mL). Thereaction mixture was heated at 70° C. overnight. The reaction mixturewas cooled to room temperature and diluted with ethyl acetate. Theorganic phase was washed with water, brine, dried over anhydrous sodiumsulfate, filtered, and concentrated. The crude material was purified byflash column purification with 0-5% ethyl acetate/hexane to afford thetitle compound.

Example 213B methyl2-(1H-indol-4-yloxy)-4-(4-((4-(2-(tert-butyldimethylsilyloxy)ethoxy)-4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was made by substituting EXAMPLE 213A for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 213C2-(1H-indol-4-yloxy)-4-(4-((4-(2-(tert-butyldimethylsilyloxy)ethoxy)-4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 213B for EXAMPLE 1D inEXAMPLE 1E.

Example 213D2-(1H-indol-4-yloxy)-4-(4-((4-(2-(tert-butyldimethylsilyloxy)ethoxy)-4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide

This example was prepared by substituting EXAMPLE 213C for EXAMPLE 1E inEXAMPLE 1G.

Example 213E4-(4-{[4′-chloro-4-(2-hydroxyethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 213D for EXAMPLE 195Bin EXAMPLE 195C. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.24 (m, 1H),8.62 (t, 1H), 8.50 (d, 1H), 7.67 (dd, 1H), 7.54 (m, 1H), 7.43 (d, 2H),7.37 (d, 2H), 7.28 (m, 1H), 7.15 (m, 2H), 7.05 (m, 2H), 6.96 (m, 1H),6.90 (dd, 1H), 6.73 (dd, 1H), 6.40 (d, 1H), 6.31 (m, 1H), 6.27 (m, 1H),4.82 (t, 1H), 3.99 (t, 2H), 3.86 (m, 2H), 3.71 (m, 2H), 3.26 (m, 6H),2.66 (m, 2H), 2.31 (m, 5H), 1.89 (m, 1H), 1.63 (m, 2H), 1.27 (m, 2H).

Example 2144-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamideExample 214A tert-butyl 1-(cyclopropylmethyl)piperidin-4-ylcarbamate

This example was prepared by substituting cyclopropanecarbaldehyde for4′-chlorobiphenyl-2-carboxaldehyde and tert-butylpiperidin-4-ylcarbamate for tert-butyl piperazine-1-carboxylate inEXAMPLE 1A.

Example 214B 1-(cyclopropylmethyl)piperidin-4-aminebis(2,2,2-trifluoroacetate)

This example was prepared by substituting EXAMPLE 214A for EXAMPLE 1A inEXAMPLE 1B.

Example 214C4-(1-(cyclopropylmethyl)piperidin-4-ylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting EXAMPLE 214B for1-(2-Methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A.

Example 214D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 214C for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz, pyridine-ds)δ 12.28 (s, 1H), 9.30 (d, 1H), 8.49 (d, 1H), 8.34 (dd, 1H), 8.18 (d,1H), 7.52-7.56 (m, 2H), 7.41-7.46 (m, 3H), 7.09 (dd, 1H), 7.06 (d, 2H),6.91 (d, 1H), 6.73 (dd, 1H), 6.61 (d, 1H), 6.54 (d, 1H), 3.45-3.56 (m,1H), 3.00-3.08 (m, 4H), 2.87 (d, 2H), 2.76 (s, 2H), 2.25 (t, 2H), 2.19(d, 4H), 2.09-2.14 (m, 4H), 1.97 (s, 4H), 1.63-1.73 (m, 2H), 1.38 (t,2H), 0.84-0.91 (m, 1H), 0.43-0.50 (m, 2H), 0.11 (q, H).

Example 2154-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamideExample 215A4-(4-methylpiperazin-1-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

This example was prepared by substituting 4-methylpiperazin-1-amine for(tetrahydropyran-4-yl)methanamine and EXAMPLE 159C for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 1F.

Example 215B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 215A for EXAMPLE 1Fand EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.21 (br s, 1H), 8.09 (m, 1H), 7.98 (m, 1H),7.83 (dd, 1H), 7.53 (d, 1H), 7.45 (d, 1H), 7.34 (d, 2H), 7.26 (t, 1H),7.16 (d, 1H), 7.04 (d, 2H), 6.97 (t, 1H), 6.66 (dd, 1H), 6.39 (d, 1H),6.24 (m, 2H), 2.87 (m, 13H), 2.38 (s, 3H), 2.17 (m, 6H), 1.95 (s, 2H),1.39 (t, 2H), 0.93 (s, 6H)

Example 2164-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(4,4,4-trifluorobutyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 210A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.13 (s, 1H), 10.89 (br s, 1H), 8.55 (d, 1H),8.22 (d, 1H), 7.79 (dd, 1H), 7.50 (d, 1H), 7.34 (m, 4H), 7.07 (m, 4H),6.83 (dd, 1H), 6.63 (dd, 1H), 6.37 (m, 1H), 6.15 (d, 1H), 3.71 (m, 1H),3.01 (m, 4H), 2.92 (m, 2H), 2.72 (s, 2H), 2.40 (m, 2H), 2.30 (m, 2H),2.16 (m, 6H), 1.95 (m, 4H), 1.68 (m, 4H), 1.38 (t, 2H), 1.24 (br s, 1H),0.92 (s, 6H).

Example 2174-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 177 by replacingEXAMPLE 26C and EXAMPLE 1F with EXAMPLE 175E and EXAMPLE 174A,respectively. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.21 (s, 1H),9.15 (s, 1H), 8.45 (d, 1H), 7.70 (dd, 1H), 7.43-7.56 (m, 5H), 7.34-7.41(m, 1H), 7.24-7.31 (m, 4H), 7.10-7.16 (m, 2H), 6.94 (t, 1H), 6.66 (dd,1H), 6.37 (d, 1H), 6.24 (dd, 2H), 2.80-3.02 (m, 10H), 2.28-2.39 (m, 5H),2.14-2.24 (m, 2H), 1.16 (d, 3H).

Example 2184-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 218A 2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enecarbaldehyde

This example was prepared by substituting EXAMPLE 18C for EXAMPLE 143Cin EXAMPLE 143D.

Example 218B tert-butyl4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)-3-(hydroxymethyl)piperazine-1-carboxylate

This example was prepared by substituting EXAMPLE 218A for EXAMPLE 27Cand tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 218C(1-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-2-yl)methanol

This example was prepared by substituting EXAMPLE 218B for EXAMPLE 1A inEXAMPLE 1B.

Example 218D ethyl2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)-3-(hydroxymethyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 218C for EXAMPLE 20Cand EXAMPLE 26A for EXAMPLE 20A in EXAMPLE 20D.

Example 218E2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)-3-(hydroxymethyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 218D for EXAMPLE 1D inEXAMPLE 1E.

Example 218F4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 218E for EXAMPLE 26Cand EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.07 (s, 1H), 8.50 (d, 1H), 8.14 (d, 1H), 7.45(d, J=9.46 Hz, 1H), 7.52 (d, 1H), 7.32-7.35 (m, 4H), 6.99-7.05 (m, 4H),6.78 (dd, 1H), 6.58-6.59 (m, 1H), 6.34 (s, 1H), 6.14 (d, 1H), 4.42-4.44(m, 1H), 3.72 (br s, 1H), 3.10-3.25 (m, 6H), 3.00 (br, 2H), 2.58-2.69(m, 6H), 1.82-2.01 (m, 6H), 1.70 (br, 2H), 1.36-1.39 (m, 2H), 0.92 (s,6H).

Example 2194-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 218E for EXAMPLE 26Cand EXAMPLE 173C for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.11 (s, 1H), 8.52 (d, 1H), 8.20 (d, 1H), 7.77(dd, 1H), 7.52 (d, 1H), 7.32-7.38 (m, 4H), 7.03-7.07 (m, 4H), 6.81 (dd,1H), 6.58-6.60 (m, 1H), 6.36 (s, 1H), 6.14 (d, 1H), 4.44 (s, 1H), 3.92(dd, 2H), 3.71 (br s, 1H), 3.41-3.43 (m, 2H), 3.02-3.06 (m, 4H),2.55-2.72 (m, 6H), 2.18-2.24 (m, 2H), 1.91-2.00 (m, 8H), 1.76-1.80 (m,2H), 1.63-1.65 (m, 2H), 1.49-1.51 (m, 2H), 1.35-1.38 (m, 2H), 0.92 (s,6H).

Example 2204-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 215A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.14 (s, 1H),8.15 (d, 1H), 8.04 (s, 1H), 7.95 (dd, 1H), 7.50 (t, 2H), 7.35 (m, 4H),7.12 (d, 1H), 7.04 (d, 2H), 6.83 (dd, 1H), 6.61 (dd, 1H), 6.39 (m, 1H),6.12 (d, 1H), 2.92 (m, 10H), 2.71 (s, 2H), 2.35 (s, 3H), 2.17 (m, 6H),1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 2214-(4-{[4′-chloro-4-(2-hydroxyethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 221A2-(1H-indol-4-yloxy)-4-(4-((4-(2-(tert-butyldimethylsilyloxy)ethoxy)-4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)-N-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonyl)benzamide

This example was prepared by substituting EXAMPLE 213C for EXAMPLE 1Eand EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G.

Example 221B4-(4-{[4′-chloro-4-(2-hydroxyethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 221A for EXAMPLE 195Bin EXAMPLE 195. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.12 (s, 1H),8.42 (d, 1H), 8.10 (d, 1H), 7.74 (dd, 1H), 7.58 (d, 1H), 7.40 (m, 4H),7.21 (m, 1H), 7.06 (m, 4H), 6.90 (m, 2H), 6.65 (m, 1H), 6.31 (d, 1H),6.23 (m, 2H), 4.84 (t, 1H), 4.00 (t, 2H), 3.71 (m, 3H), 3.24 (m, 4H),3.02 (m, 6H), 2.66 (m, 2H), 2.32 (m, 5H), 2.00 (m, 2H), 1.69 (m, 2H).

Example 2224-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamideExample 222A3-nitro-4-[3-(3-oxo-piperazin-1-yl)-propylamino]-benzenesulfonamide

4-(3-Amino-propyl)-piperazin-2-one (3.45 g) and triethylamine (5.18 mL,3.76 g) were added to 1,4-dioxane (100 mL) and N,N-dimethylacetamide (20mL) and mixed until dissolved. 4-Chloro-3-nitrobenzenesulfonamide (4.00g) was added, and the mixture was heated to 90° C. for 16 hours. Themixture was cooled and the solvent was removed under vacuum. Thematerial purified by recrystallization from 20% methanol indichloromethane with subsequent washing of the recrystallized solid with10% methanol in dichloromethane followed by washing with 100%dichloromethane.

Example 222B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 222A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.16 (br s, 1H), 8.85 (t, 1H), 8.58 (d, 1H),7.79 (dd, 1H), 7.74 (br s, 1H), 7.51 (d, 1H), 7.43-7.37 (m, 2H), 7.34(d, 2H), 7.16 (d, 1H), 7.07-7.01 (m, 3H), 6.86 (dd, 1H), 6.65, (d, 1H),6.39 (t, 1H), 6.15 (d, 1H), 3.43 (q, 2H), 3.17 (t, 2H), 3.03 (m, 4H),2.95 (s, 2H), 2.72 (s, 2H), 2.56 (t, 2H), 2.47 (t, 2H), 2.16 (m, 6H),1.95 (br s, 2H), 1.79 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 2234-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 1E andEXAMPLE 222A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.24 (br s, 1H), 8.83 (t, 1H), 8.50 (d, 1H),7.75 (br s, 1H), 7.68 (dd, 1H), 7.53 (d, 1H), 7.34 (d, 2H), 7.28 (t,1H), 7.18 (d, 1H), 7.04 (d, 2H), 7.02-6.94 (m, 2H), 6.71 (dd, 1H), 6.42(d, 1H), 6.29-6.23 (m, 2H), 3.43 (q, 2H), 3.17 (m, 2H), 3.05 (m, 4H),2.96 (s, 2H), 2.72 (s, 2H), 2.57 (t, 2H), 2.48 (t, 2H), 2.17 (m, 6H),1.95 (br s, 2H), 1.79 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 2244-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 224A 2-chloro-5-hydroxycyclohex-1-enecarbaldehyde

Phosphorus oxychloride (4.08 mL) was added to cooled (−10° C.)N,N-dimethylformamide (20 mL). The temperature was maintained below 0°C. Stirring was continued for another 30 minutes before the addition of4-(tert-butyldimethylsilyloxy)cyclohexanone (10 g). The mixture was thenstirred at room temperature for 2 hours before it was diluted with ethylacetate (300 mL) and washed with water (3×), brine and dried overNa₂SO₄. After filtration and concentration, the crude product was useddirectly in the next reaction without further purification.

Example 224B 2-(4-chlorophenyl)-5-hydroxycyclohex-1-enecarbaldehyde

To a mixture of 4-chlorophenylboronic acid (6.88 g), EXAMPLE 224A (4.65g), palladium(II) acetate (131 mg), K₂CO₃ (18.24 g) andtetrabutylammonium bromide (14.18 g) was added water (200 mL). Themixture was stirred at 50° C. for 4 hours, cooled, and diluted withethyl acetate (400 mL) and washed with water (3×) and brine and driedover Na₂SO₄. After filtration and concentration, the residue was loadedon a column and eluted with 5-20% ethyl acetate in hexane to give thetitle compound.

Example 224C methyl2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5-hydroxycyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

To a mixture of EXAMPLE 224B (0.8 g) and EXAMPLE 150A (1.2 g) indichloromethane (20 mL) was added sodium triacetoxyborohydride (1.2 g).The mixture was stirred overnight. The mixture was diluted with ethylacetate (200 mL) and washed with 2% NaOH, water and brine. After dryingover Na₂SO₄, the solvent was evaporated under vacuum and the residue wasloaded on a column and eluted with 5-10% methanol in dichloromethane togive the title compound.

Example 224D2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5-hydroxycyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

To a mixture of EXAMPLE 224C (1.78 g) in tetrahydrofuran (30 mL),methanol (10 mL) and water (10 mL) was added LiOH.H₂O (0.262 g). Themixture was stirred overnight. The mixture was then neutralized with 5%aqueous HCl and exacted with ethyl acetate (3×) and the combined organiclayers were washed with brine and dried over Na₂SO₄. Evaporation ofsolvent gave the title compound.

Example 224E4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 224D for EXAMPLE 1Eand EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.08 (s, 1H), 8.50 (d, 1H), 8.13 (d, 1H), 7.77(dd, 1H), 7.52 (d, 1H), 7.34 (m, 4H), 7.04 (m, 4H), 6.78 (dd, 1H), 6.59(dd, 1H), 6.35 (s, 1H), 6.13 (d, 1H), 4.59 (d, 1H), 3.74 (m, 2H), 3.39(m, 1H), 3.03 (m, 7H), 2.68 (m, 3H), 2.41 (m, 4H), 2.17 (m, 7H), 2.00(m, 3H), 1.71 (m, 3H).

Example 2254-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 224D for EXAMPLE 1Eand EXAMPLE 173C for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.07 (s, 1H), 8.47 (d, 1H), 8.14 (d, 1H), 7.92(s, 1H), 7.72 (dd, 1H), 7.52 (d, 1H), 7.46 (d, 1H), 7.33 (m, 4H), 7.07(d, 2H), 6.98 (d, 1H), 6.77 (m, 1H), 6.58 (dd, 1H), 6.34 (s, 1H), 6.14(d, 1H), 4.59 (m, 1H), 3.90 (dd, 2H), 3.70 (m, 1H), 3.01 (m, 8H), 2.71(m, 6H), 2.56 (m, 8H), 2.19 (m, 4H), 1.94 (m, 3H), 1.56 (m, 3H).

Example 2264-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 224D for EXAMPLE 1Eand EXAMPLE 174A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.13 (s, 1H), 9.13 (s, 1H), 8.52 (d, 1H), 7.83(dd, 1H), 7.53 (t, 2H), 7.36 (m, 4H), 7.09 (m, 3H), 6.83 (dd, 1H), 6.61(dd, 1H), 6.38 (s, 1H), 6.12 (d, 1H), 4.59 (d, 1H), 3.75 (m, 1H), 2.81(m, 12H), 2.27 (m, 12H), 1.79 (m, 4H).

Example 2274-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamideExample 227A4-(1-indan-2-yl-piperidin-4-ylamino)-3-nitro-benzenesulfonamide

2-Aminoindane (12.84 g) and triethylamine (15.04 mL, 10.92 g) were addedto 1,4-dioxane (150 mL) and the mixture was stirred until the solidswere dissolved. 4-Chloro-3-nitrobenzenesulfonamide (12.77 g) was added,and the mixture was heated to 90° C. for 16 hours. The mixture wascooled and the precipitate vacuum was filtered, washed with 20% methanolin dichloromethane, and washed with 100% dichloromethane.

Example 227B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 1E andEXAMPLE 227A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.20 (br s, 1H), 8.48 (d, 1H), 8.21 (d, 1H),7.73 (dd, 1H), 7.54 (d, 1H), 7.34 (d, 2H), 7.26-7.21 (m, 3H), 7.16-7.12(m, 2H), 7.09-7.02 (m, 3H), 6.95 (t, 2H), 6.68 (dd, 1H), 6.39 (d, 1H),6.24 (m, 2H), 3.74 (m, 1H), 3.18-2.80 (m, 13H), 2.72 (br s, 2H), 2.16(m, 6H), 2.03 (m, 2H), 1.95 (br s, 2H), 1.68 (m, 2H), 1.38 (t, 2H), 0.92(s, 6H).

Example 2284-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 227A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.12 (br s, 1H), 8.55 (d, 1H), 8.23 (d, 1H),7.79 (dd, 1H), 7.51 (d, 1H), 7.41-7.31 (m, 4H), 7.22 (m, 2H), 7.16-7.09(m, 3H), 7.07-7.01 (m, 3H), 6.83 (dd, 1H), 6.63 (dd, 1H), 6.37 (t, 1H),6.15 (d, 1H), 3.73 (m, 1H), 3.16-2.82 (m, 13H), 2.71 (br s, 2H), 2.16(m, 6H), 2.02 (m, 2H), 1.95 (br s, 2H), 1.67 (m, 2H), 1.38 (t, 2H), 0.92(s, 6H).

Example 2294-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1-morpholin-4-ylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting(1-morpholinocyclohexyl)methanamine for(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in EXAMPLE187B. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.19 (s, 1H), 9.08 (s,1H), 8.60 (d, 1H), 7.81 (dd, 1H), 7.51 (d, 1H), 7.43 (d, 1H), 7.39 (t,1H), 7.33 (d, 2H), 7.16-7.18 (m, 2H), 7.03 (d, 2H), 6.88 (dd, 1H), 6.65(dd, 1H), 6.40 (s, 1H), 6.13 (d, 1H), 3.60 (s, 4H), 3.42-3.43 (m, 2H),3.01 (br s, 4H), 2.72 (br s, 2H), 2.57 (br s, 4H), 2.12-2.16 (m, 7H),1.94 (br s, 2H), 1.46-1.60 (m, 12H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).

Example 2304-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-2-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamideExample 230A tert-butyl 1-(thiazol-2-ylmethyl)piperidin-4-ylcarbamate

This example was prepared by substituting thiazole-2-carbaldehyde forEXAMPLE 27C and tert-butyl piperidin-4-ylcarbamate for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 230B 1-(thiazol-2-ylmethyl)piperidin-4-amine

This example was prepared by substituting EXAMPLE 230A for EXAMPLE 1A inEXAMPLE 1B.

Example 230C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-2-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 230B for(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in EXAMPLE187B. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.14 (s, 1H), 8.23 (d,1H), 7.76-7.79 (m, 2H), 7.65 (s, 1H), 7.53 (d, 1H), 7.38-7.40 (m, 2H),7.34 (d, 2H), 7.17 (d, 1H), 7.11 (s, 1H), 7.04 (d, 2H), 6.82 (dd, 1H),6.62 (d, 1H), 6.38 (s, 1H), 6.14 (d, 1H), 4.19 (s, 2H), 3.01 (s, 4H),2.91-2.96 (m, 2H), 2.72 (s, 2H), 2.12-2.17 (m, 6H), 1.95-1.99 (m, 4H),1.47-1.51 (m, 2H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).

Example 2314-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamideExample 231A tert-butyl 1-(thiazol-4-ylmethyl)piperidin-4-ylcarbamate

This example was prepared by substituting thiazole-4-carbaldehyde forEXAMPLE 27C and tert-butyl piperidin-4-ylcarbamate for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 231B 1-(thiazol-4-ylmethyl)piperidin-4-amine

This example was prepared by substituting EXAMPLE 231A for EXAMPLE 1A inEXAMPLE 1B.

Example 231C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 231B for(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in EXAMPLE187B. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.11 (s, 1H), 9.06 (s,1H), 8.21 (d, 1H), 7.98 (s, 1H), 7.77 (dd, 1H), 7.54 (d, 1H), 7.33-7.38(m, 4H), 7.13 (d, 2H), 7.03-7.07 (m, 3H), 6.79 (dd, 1H), 6.60 (dd, 1H),6.37 (s, 1H), 6.14 (d, 1H), 4.23 (s, 2H), 2.99 (s, 4H), 2.89-2.94 (m,2H), 2.71 (s, 2H), 2.12-2.17 (m, 6H), 1.95-1.99 (m, 4H), 1.47-1.51 (m,2H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).

Example 2324-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)methanol for(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in EXAMPLE187B. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 1H), 9.10 (t,1H), 8.59 (d, 1H), 7.81 (dd, 1H), 7.51 (d, 1H), 7.42 (d, 1H), 7.39 (t,1H), 7.16-7.18 (m, 2H), 7.03 (d, 2H), 6.87 (dd, 1H), 6.65 (d, 1H), 6.39(s, 1H), 6.14 (d, 1H), 5.22 (t, 1H), 3.51-3.62 (m, 6H), 3.19 (d, 2H),3.03 (s, 4H), 2.72 (s, 2H), 2.12-2.17 (m, 6H), 1.94 (s, 2H), 1.45-1.49(m, 4H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).

Example 2334-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(2-hydroxyethyl)piperazin-1-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamideExample 233A4-(4-(2-hydroxyethyl)piperazin-1-ylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting2-(4-aminopiperazin-1-yl)ethanol for(tetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 1F.

Example 233B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(2-hydroxyethyl)piperazin-1-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 233A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.15 (s, 1H),9.17 (m, 1H), 8.53 (d, 1H), 7.83 (dd, 1H), 7.56 (d, 1H), 7.51 (d, 1H),7.36 (m, 4H), 7.13 (m, 1H), 7.03 (m, 2H), 6.84 (dd, 1H), 6.62 (dd, 1H),6.38 (m, 1H), 6.12 (m, 1H), 4.57 (m, 1H), 3.54 (m, 2H), 2.95 (m, 10H),2.71 (s, 2H), 2.57 (m, 2H), 2.15 (m, 6H), 1.94 (s, 2H), 1.38 (t, 2H),0.93 (s, 6H)

Example 2344-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamideExample 234A (S)-tert-butyl 1-methylpyrrolidin-3-ylcarbamate

To a mixture of (S)-tert-butyl 1-methylpyrrolidin-3-ylcarbamate (438 mg)in methanol (10 mL) was added 37% formaldehyde mixture in water (0.53mL) and sodium borohydride (267 mg). The reaction mixture was stirredovernight at room temperature and then concentrated. The residue wasdissolved in chloroform (15 mL), washed with brine and NaHCO₃ solution,dried over MgSO₄, filtered and concentrated. The title compound was usedin the next step without further purification.

Example 234B (S)-1-methylpyrrolidin-3-amine

This example was prepared by substituting EXAMPLE 234A for EXAMPLE 1A inEXAMPLE 1B.

Example 234C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 234B for1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 310B for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 10.98 (s, 1H), 8.38 (d, 1H), 8.16 (d, 1H), 7.64(dd, 1H), 7.53 (d, 1H), 7.34 (d, 2H), 7.28 (m, 2H), 7.05 (d, 2H), 6.89(d, 1H), 6.72 (d, 1H), 6.68 (dd, 1H), 6.53 (dd, 1H), 6.29 (t, 1H), 6.15(d, 1H), 4.14 (br s, 1H), 2.93 (m, 4H), 2.71 (m, 4H), 2.33 (m, 2H), 2.27(s, 3H), 2.16 (m, 6H), 1.95 (s, 2H), 1.61 (m, 1H), 1.38 (t, 2H), 1.24(br s, 1H), 0.92 (s, 6H).

Example 2354-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(3-fluoropropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamideExample 235A4-(1-(3-fluoropropyl)piperidin-4-ylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting 1-fluoro-3-iodopropane for1,1,1-trifluoro-4-iodobutane in EXAMPLE 210A.

Example 235B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(3-fluoropropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 235A for EXAMPLE 1Fand EXAMPLE 26C for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.12 (s, 1H), 10.89 (br s, 1H), 8.48 (d, 1H),8.152 (d, 1H), 7.79 (dd, 1H), 7.50 (d, 1H), 7.34 (m, 4H), 7.03 (m, 4H),6.83 (dd, 1H), 6.63 (dd, 1H), 6.37 (m, 1H), 6.15 (d, 1H), 3.71 (br s,1H), 3.01 (m, 4H), 2.92 (m, 2H), 2.72 (m, 2H), 2.56 (m, 1H), 2.30 (m,2H), 2.16 (m, 6H), 1.95 (m, 5H), 1.83 (m, 1H), 1.68 (m, 2H), 1.38 (m,2H), 1.24 (br s, 1H), 0.92 (s, 6H).

Example 2364-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 218E for EXAMPLE 26Cin EXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 2H),8.62 (s, 1H), 8.58 (s, 1H), 7.78 (d, 1H), 7.52 (d, 1H), 7.39-7.42 (m,2H), 7.33 (d, 1H), 7.14 (s, 1H), 7.09 (d, 1H), 7.04 (d, 1H), 6.86 (d,1H), 6.62 (d, 1H), 6.39 (s, 1H), 6.14 (s, 1H), 4.46 (m, 1H), 3.85 (dd,2H), 3.17-3.25 (m, 8H), 2.76 (br s, 2H), 2.58 (br s. 2H), 1.89-2.01 (m,6H), 1.80 (br, 2H), 1.29-1.38 (m, 2H), 0.91 (s, 6H).

Example 237N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)benzamideExample 237A4-((4-aminotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting4-(aminomethyl)tetrahydro-2H-pyran-4-amine for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 237BN-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 218E for EXAMPLE 26Cand EXAMPLE 237A for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.46 (s, 1H), 11.19 (s, 1H), 8.16 (d, 1H),8.51-8.55 (m, 1H), 8.11 (s, 2H), 7.88 (d, 1H), 7.53 (d, 1H), 7.32-7.43(m, 5H), 7.15 (s, 1H), 7.09 (d, 1H), 6.85 (dd, 1H), 6.68 (s, 1H), 6.40(s, 1H), 6.21 (s, 1H), 3.81-3.82 (m, 2H), 3.70-3.72 (m, 4H), 3.10 (br s,2H), 2.02-2.09 (m, 2H), 1.60-1.85 (m, 2H), 1.66-1.73 (m, 2H), 1.35-1.38(m, 2H), 0.93 (s, 6H).

Example 2384-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting 1-(aminomethyl)cyclohexanolfor (3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in EXAMPLE187B. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 2H), 8.69 (t,1H), 8.60 (d, 1H), 7.80 (dd, 1H), 7.51 (d, 1H), 7.39-7.43 (m, 2H), 7.33(d, 2H), 7.17 (d, 2H), 7.14 (d, 1H), 7.03 (d, 2H), 6.87 (dd, 1H), 6.65(d, 1H), 6.40 (s, 1H), 6.14 (d, 1H), 4.73 (s, 1H), 3.03 (s, 4H), 2.74(s, 2H), 2.12-2.18 (m, 6H), 1.94 (s, 2H), 1.54-1.58 (m, 4H), 1.36-1.43(m, 7H), 0.92 (s, 6H).

Example 2394-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 179A for EXAMPLE 1Fand EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.25 (s, 2H), 8.57 (m, 1H), 8.50 (d, 1H), 7.70(dd, 1H), 7.52 (d, 1H), 7.34 (d, 2H), 7.28 (t, 1H), 7.17 (d, 1H), 7.05(m, 3H), 6.97 (t, 1H), 6.71 (dd, 1H), 6.42 (d, 1H), 6.26 (m, 2H), 3.58(m, 4H), 3.31 (s, 3H), 3.05 (m, 4H), 2.73 (s, 2H), 2.17 (m, 6H), 1.96(s, 2H), 1.38 (t, 2H), 0.93 (s, 6H)

Example 2404-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamideExample 240A4-(4-(hydroxymethyl)tetrahydro-2H-pyran-4-ylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting(4-aminotetrahydro-2H-pyran-4-yl)methanol for(tetrahydropyran-4-yl)methylamine and 4-fluoro-3-nitrobenzenesulfonamidefor 4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 1F.

Example 240B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 240A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.14 (s, 2H),8.63 (d, 1H), 8.50 (s, 1H), 7.92 (s, 1H), 7.79 (dd, 1H), 7.52 (d, 1H),7.39-7.43 (m, 2H), 7.33-7.34 (m, 3H), 7.18 (s, 1H), 7.03 (d, 2H), 6.87(dd, 1H), 6.65 (dd, 1H), 6.40 (s, 1H), 6.13 (d, 1H), 5.04 (t, 1H),3.67-3.72 (m, 4H), 3.56 (t, 2H), 3.02 (s, 4H), 2.72 (br, 2H), 2.12-2.16(m, 6H), 1.94-2.01 (m, 3H), 1.81-1.85 (m, 2H), 1.36-1.39 (m, 2H), 1.24(m, 6H), 0.92 (s, 6H).

Example 2414-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 240A for EXAMPLE 1Fand EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.26 (s, 2H), 8.55 (d, J=2.14 Hz, 1H), 8.48 (s,1H), 7.66 (dd, 1H), 7.54 (d, 1H), 7.34 (d, 2H), 7.27-7.29 (m, 2H), 7.19(d, 2H), 7.03 (d, 2H), 6.99 (t, 1H), 6.70 (dd, 1H), 6.44 (d, 1H), 6.27(s, 1H), 5.04 (t, 1H), 3.67-3.72 (m, 4H), 3.56 (t, 2H), 3.04 (s, 4H),2.74 (s, 2H), 2.12-2.17 (m, 6H), 1.95-2.01 (m, 5H), 1.80-1.85 (m, 2H),1.38 (t, 2H), 1.24 (m, 4H), 0.92 (s, 6H).

Example 2424-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-hydroxy-1-tetrahydro-2H-pyran-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting2-amino-2-(tetrahydro-2H-pyran-4-yl)ethanol for(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in EXAMPLE187B. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.18 (s, 1H), 8.60 (d,1H), 8.57 (d, 1H), 7.79 (dd, 1H), 7.52 (d, 1H), 7.43 (d, 1H), 7.40 (t,1H), 7.33 (d, 2H), 7.23 (d, 1H), 7.19 (d, 1H), 7.03 (d, 2H), 6.88 (dd,1H), 6.65 (dd, 1H), 6.41 (s, 1H), 6.13 (d, 1H), 5.03 (t, 1H), 3.83-3.87(m, 2H), 3.56-3.73 (m, 4H), 3.26 (t, 2H), 3.03 (s, 4H), 2.72 (s, 2H),2.12-2.17 (br s, 4H), 1.58-1.62 (m, 2H), 1.36-1.39 (m, 2H), 0.92 (s,6H).

Example 2434-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-({1-[2-(1H-pyrazol-1-yl)ethyl]piperidin-4-yl}amino)phenyl]sulfonyl}benzamideExample 243A4-(1-(2-(1H-pyrazol-1-yl)ethyl)piperidin-4-ylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting 1-(2-bromoethyl)-1H-pyrazolefor 1,1,1-trifluoro-4-iodobutane in EXAMPLE 210A. After concentratingthe reaction mixture, the title compound was collected by filtration ofthe ether slurry.

Example 243B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-({1-[2-(1H-pyrazol-1-yl)ethyl]piperidin-4-yl}amino)phenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 243A for EXAMPLE 1Fand EXAMPLE 26C for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.25 (br s, 1H), 11.14 (s, 1H), 8.55 (d, 1H),8.22 (d, 1H), 7.74 (m, 2H), 7.50 (d, 1H), 7.40 (m, 3H), 7.33 (d, 2H),7.10 (m, 1H), 7.03 (d, 2H), 6.83 (dd, 1H), 6.63 (dd, 1H), 6.38 (t, 1H),6.22 (t, 1H), 6.15 (d, 1H), 4.24 (t, 2H), 3.65 (br s, 1H), 3.02 (m, 4H),2.78 (m, 6H), 2.27 (m, 2H), 2.16 (m, 6H), 1.94 (m, 3H), 1.60 (m, 2H),1.38 (t, 2H), 1.23 (br s, 1H), 0.92 (s, 6H).

Example 2444-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 26 Cin EXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.26 (s, 2H),8.61 (t, 1H), 8.50 (d, 1H), 7.69 (dd, 1H), 7.28 (t, 1H), 7.18 (d, 2H),7.07 (d, 1H), 7.04 (d, 2H), 6.97 (t, 1H), 6.71 (dd, 1H), 6.43 (d, 1H),6.28 (d, 1H), 6.26 (d, 1H), 5.04 (t, 1H), 3.85 (dd, 2H), 3.25-3.31 (m,6H), 3.05 (s, 4H), 2.74 (s, 2H), 2.14-2.18 (m, 6H), 1.87-1.90 (m, 2H),1.61-1.63 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 2454-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(methylamino)-3-nitrophenyl]sulfonyl}benzamideExample 245A 4-(methylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting methanamine for(tetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 1F.

Example 245B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(methylamino)-3-nitrophenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 245A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.12 (m, 2H),8.54 (m, 2H), 7.76 (m, 1H), 7.51 (d, 1H), 7.35 (m, 4H), 7.06 (m, 3H),6.85 (m, 2H), 6.63 (d, 1H), 6.37 (m, 1H), 6.15 (d, 1H), 3.01 (m, 4H),2.96 (d, 3H), 2.71 (s, 2H), 2.15 (m, 6H), 1.94 (s, 2H), 1.38 (t, 2H),0.92 (s, 6H)

Example 2464-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(methylamino)-3-nitrophenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 245A for EXAMPLE 1Fand EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.32 (br s, 1H), 11.20 (br s, 1H), 8.54 (br s,1H), 8.46 (s, 1H), 7.70 (dd, 1H), 7.53 (d, 1H), 7.34 (d, 2H), 7.26 (m,1H), 7.14 (d, 1H), 7.04 (d, 2H), 6.94 (t, 1H), 6.87 (m, 1H), 6.67 (m,1H), 6.37 (m, 1H), 6.25 (m, 2H), 3.02 (m, 4H), 2.97 (d, 3H), 2.72 (s,2H), 2.16 (m, 6H), 1.94 (s, 2H), 1.38 (t, 2H), 0.93 (s, 6H).

Example 2474-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 175E for EXAMPLE 1Eand EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz,PYRIDINE-d₅) δ ppm 12.45 (s, 1H), 9.24 (d, 1H), 8.96 (t, 1H), 8.26 (dd,1H), 8.16 (d, 1H), 7.65 (d, 1H), 7.46 (m, 5H), 7.35 (t, 1H), 7.30 (d,2H), 7.24 (d, 1H), 7.15 (t, 1H), 6.86 (d, 1H), 6.79 (d, 1H), 6.74 (m,2H), 6.61 (d, 1H), 3.78 (t, 4H), 3.41 (q, 1H), 3.31 (m, 2H), 2.94 (m,4H), 2.34 (m, 6H), 2.24 (m, 2H), 2.10 (m, 2H), 1.72 (m, 2H), 1.15 (d,3H).

Example 2484-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 224D for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 1H), 8.60(m, 1H), 7.80 (dd, 1H), 7.52 (d, 1H), 7.38 (m, 4H), 7.11 (m, 4H), 6.87(dd, 1H), 6.65 (dd, 1H), 6.40 (s, 1H), 6.13 (d, 1H), 4.59 (d, 1H), 3.85(m, 2H), 3.28 (m, 6H), 3.03 (m, 2H), 2.72 (m, 2H), 2.18 (m, 3H), 1.87(m, 3H), 1.53 (m, 5H), 1.26 (m, 7H).

Example 2494-(4-{[2-(4-chlorophenyl)-5-morpholin-4-ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 249A 8-chloro-1,4-dioxaspiro[4.5]dec-7-ene-7-carbaldehyde

This example was prepared by substituting 1,4-dioxaspiro[4.5]decan-8-onefor 4-(tert-butyldimethylsilyloxy)cyclohexanone in EXAMPLE 224A.

Example 249B8-(4-chlorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene-7-carbaldehyde

This example was prepared by substituting EXAMPLE 249A for EXAMPLE 224Ain EXAMPLE 224B.

Example 249C methyl2-(1H-indol-5-yloxy)-4-(4-((8-(4-chlorophenyl)-1,4-dioxaspiro[4.5]dec-7-en-7-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 249B for EXAMPLE 224Bin EXAMPLE 224C.

Example 249D2-(1H-indol-5-yloxy)-4-(4-((8-(4-chlorophenyl)-1,4-dioxaspiro[4.5]dec-7-en-7-yl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared by substituting EXAMPLE 249C for EXAMPLE224C in EXAMPLE 224D.

Example 249E2-(1H-indol-5-yloxy)-4-(4-((8-(4-chlorophenyl)-1,4-dioxaspiro[4.5]dec-7-en-7-yl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide

This example was prepared by substituting EXAMPLE 249D for EXAMPLE 1E inEXAMPLE 1G.

Example 249F2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5-oxocyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide

A mixture of EXAMPLE 249E (20 mg) and pyridinium p-toluenesulfonate(16.8 mg) in acetone/H₂O (1:1, 3 mL) was heated in a microwave to 135°C. for 8 minutes. The mixture was diluted with dichloromethane (100 mL),washed with water and brine, and dried over Na₂SO₄. Filtration andevaporation of solvent gave the product.

Example 249G4-(4-{[2-(4-chlorophenyl)-5-morpholin-4-ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

To a mixture of EXAMPLE 249F (120 mg) in dichloromethane (2 mL) andmethanol (0.5 mL) was added morpholine (37 mg) and 2-picoline boranecomplex (15.04 mg). The mixture was stirred overnight. The mixture wasthen diluted with dichloromethane (200 mL) and washed with aqueousNaHCO₃, water, and brine, and dried over Na₂SO₄. The residue, afterevaporation of solvent, was dissolved in dichloromethane andchromatographed with 0-10% 7N NH₃ in 5% methanol in dichloromethane togive the title compound. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.15(s, 1H), 8.58 (m, 2H), 7.79 (dd, 1H), 7.53 (m, 1H), 7.35 (m, 4H), 7.17(m, 1H), 7.07 (m, 2H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.39 (s, 1H), 6.13(d, 1H), 3.84 (m, 2H), 3.58 (m, 5H), 3.01 (m, 5H), 2.63 (m, 6H), 2.10(m, 14H), 1.61 (m, 3H), 1.26 (m, 3H).

Example 250N-[(4-{[(1-aminocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting1-(aminomethyl)cyclohexanamine, 2 hydrochloric acid for(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in EXAMPLE187B. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.04 (s, 1H), 8.47 (d,1H), 8.39 (s, 1H), 7.79 (dd, 1H), 7.55 (d, 1H), 7.31-7.34 (m, 4H),6.99-7.08 (m, 4H), 6.73 (dd, 1H), 6.65 (dd, 1H), 6.33 (s, 1H), 6.12 (d,1H), 3.55 (d, 2H), 2.94 (s, 4H), 2.71 (s, 2H), 2.14-2.17 (m, 6H), 1.95(s, 2H), 1.50-1.64 (m, 8H), 1.36-1.39 (m, 2H), 0.92 (s, 6H).

Example 2514-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxopyrrolidin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide

This example was prepared by substituting1-(2-aminoethyl)pyrrolidin-2-one for(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in EXAMPLE187B. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 1H), 8.58-8.60(m, 2H), 7.84 (dd, 1H), 7.51 (d, 1H), 7.39-7.32 (m, 2H), 7.33 (d, 2H),7.18 (d, 1H), 7.12 (d, 1H), 7.03 (d, 2H), 6.87 (dd, 1H), 6.65 (dd, 1H),6.40 (s, 1H), 6.17 (d, 1H), 3.53-3.56 (m, 2H), 3.45 (t, 2H), 3.39 (t,2H), 3.04 (s, 4H), 2.74 (s, 2H), 2.11-2.18 (m, 8H), 1.94 (s, 2H),1.83-1.90 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 2524-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 252A methyl2-(1H-indol-5-yloxy)-4-(4-(1-(4′-chlorobiphenyl-2-yl)ethyl)piperazin-1-yl)benzoate

The title compound was prepared as described in EXAMPLE 175D byreplacing ethyl 2-(1H-indol-4-yloxy)-4-fluorobenzoate with EXAMPLE 26A.

Example 252B2-(1H-indol-5-yloxy)-4-(4-(1-(4′-chlorobiphenyl-2-yl)ethyl)piperazin-1-yl)benzoicacid

The title compound was prepared as described in EXAMPLE 175E byreplacing EXAMPLE 175D with v 252A.

Example 252C4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 175F byreplacing EXAMPLE 175E with EXAMPLE 252B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.20 (s, 1H), 11.16 (s, 1H), 8.62 (t, 1H), 8.58(d, 1H), 7.79 (dd, 1H), 7.48-7.54 (m, 2H), 7.45 (d, 2H), 7.35-7.41 (m,3H), 7.25-7.29 (m, 3H), 7.15 (d, 1H), 7.08-7.13 (m, 2H), 6.86 (dd, 1H),6.63 (dd, 1H), 6.38 (s, 1H), 6.13 (d, 1H), 3.85 (dd, 2H), 3.22-3.32 (m,4H), 3.00 (s, 4H), 2.33 (s, 2H), 2.18 (s, 2H), 1.84-1.95 (m, 1H),1.56-1.66 (m, 2H), 1.21-1.31 (m, 3H), 1.16 (d, 3H).

Example 2534-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 253A 1-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)ethanol

To a mixture of EXAMPLE 218A (3.52 g) in tetrahydrofuran (30 ml) wasslowly added methylmagnesium chloride (3 M in tetrahydrofuran, 7.08 ml)at −78° C. After the addition was completed, the reaction mixture wasstirred at 0° C. for 30 minutes and ice-water was added. The resultingmixture was extracted with dichloromethane and the organic layer wasdried over Na₂SO₄ and concentrated. The residue was purified by flashchromatography, eluting with 0-100% dichloromethane in hexane to providethe title compound.

Example 253B 1-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)ethanone

To a mixture of EXAMPLE 253A (1.18 g) in dichloromethane (20 ml) wasslowly added Dess-Martin Periodinane (2.457 g). The reaction mixture wasstirred at room temperature for 3 hours and diluted with ether. Theresulting mixture was washed with aqueous NaOH and water. The organiclayer was dried over Na₂SO₄ and concentrated. The residue was purifiedby flash chromatography, eluting with 0-100% dichloromethane in hexaneto provide the title compound.

Example 253C tert-butyl4-(1-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)ethyl)piperazine-1-carboxylate

EXAMPLE 253B (2.06 g) and tert-butyl piperazine-1-carboxylate (2.92 g)was treated with titanium(IV) isopropoxide (4.59 ml) at ambienttemperature for 24 hours. Sodium cyanoborohydride (0.493 g) in methanol(10 ml) was added. The reaction mixture was stirred overnight andaqueous NaOH was added. The resulting mixture was diluted with ethylacetate (300 ml). The precipitate was filtered off and washed with ethylacetate. The organic layer was separated and washed with brine, driedover Na₂SO₄, filtered, and concentrated. The residue was dissolved indichloromethane and loaded onto a silica gel column, eluted with 0-25%ethyl acetate in dichloromethane to provide the title compound.

Example 253D1-(1-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)ethyl)piperazine

The title compound was prepared as described in EXAMPLE 175C byreplacing EXAMPLE 175B with EXAMPLE 253C.

Example 253E ethyl2-(1H-indol-5-yloxy)-4-(4-(1-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)ethyl)piperazin-1-yl)benzoate

The title compound was prepared as described in EXAMPLE 175D byreplacing ethyl 2-(1H-indol-4-yloxy)-4-fluorobenzoate and EXAMPLE 175Cwith EXAMPLE 26A and EXAMPLE 253D, respectively.

Example 253F2-(1H-indol-5-yloxy)-4-(4-(1-(2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)ethyl)piperazin-1-yl)benzoicacid

The title compound was prepared as described in EXAMPLE 175E byreplacing EXAMPLE 175D with EXAMPLE 253E.

Example 253G4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 177 by replacingEXAMPLE 26C with EXAMPLE 253F. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ11.18 (s, 2H), 8.62 (t, 1H), 8.59 (d, 1H), 7.81 (dd, 1H), 7.52 (d, 1H),7.38-7.44 (m, 2H), 7.34 (d, 2H), 7.17 (d, 1H), 7.11 (d, 1H), 7.01 (d,2H), 6.87 (dd, 1H), 6.65 (dd, 1H), 6.40 (t, 1H), 6.13 (d, 1H), 3.85 (dd,2H), 3.22-3.31 (m, 4H), 3.02 (s, 4H), 2.57-2.73 (m, 1H), 2.23 (s, 4H),1.78-2.15 (m, 5H), 1.57-1.65 (m, 2H), 1.32-1.42 (m, 2H), 1.19-1.31 (m,2H), 1.01 (d, 3H), 0.91 (d, 6H).

Example 2544-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 175F byreplacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 253F and EXAMPLE174A. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.15 (s, 1H), 9.19 (s,1H), 8.54 (d, 1H), 7.85 (dd, 1H), 7.57 (d, 1H), 7.52 (d, 1H), 7.37-7.41(m, 2H), 7.34 (d, 2H), 7.14 (d, 1H), 7.01 (d, 2H), 6.84 (dd, 1H), 6.62(dd, 1H), 6.39 (s, 1H), 6.12 (d, 1H), 2.81-3.04 (m, 10H), 2.58-2.67 (m,1H), 2.29-2.45 (m, 5H), 2.15-2.28 (m, 4H), 1.92-2.13 (m, 3H), 1.82 (d,1H), 1.29-1.41 (m, 2H), 1.00 (d, 3H), 0.91 (d, 6H).

Example 2554-{4-[(1R)-1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was obtained by the separation of the racemic mixtureof EXAMPLE 175F on a chiral HPLC. ¹H NMR (500 MHz, dimethysulfoxide-d₆)δ 11.31 (1H, s), 11.25 (1H, s), 8.62 (1H, t), 8.50 (1H, d), 7.68 (1H,dd), 7.53 (2H, d), 7.46 (2H, d), 7.37 (1H, t), 7.24-7.31 (4H, m), 7.17(1H, d), 7.12 (1H, dd), 7.07 (1H, d), 6.96 (1H, t), 6.69 (1H, dd), 6.42(1H, d), 6.26 (2H, s), 3.85 (2H, dd), 3.21-3.33 (5H, m), 3.01 (4H, s),2.29-2.39 (2H, m), 2.15-2.22 (2H, m), 1.83-1.94 (1H, m), 1.57-1.68 (2H,m), 1.22-1.31 (2H, m), 1.17 (3H, d).

Example 2564-{4-[(1S)-1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was obtained by the separation of the racemic mixtureof EXAMPLE 175F on a chiral HPLC. ¹H NMR (500 MHz, dimethysulfoxide-d₆)δ 11.31 (1H, s), 11.25 (1H, s), 8.62 (1H, t), 8.50 (1H, d), 7.68 (1H,dd), 7.53 (2H, d), 7.46 (2H, d), 7.37 (1H, t), 7.24-7.31 (4H, m), 7.17(1H, d), 7.12 (1H, dd), 7.07 (1H, d), 6.96 (1H, t), 6.69 (1H, dd), 6.42(1H, d), 6.26 (2H, s), 3.85 (2H, dd), 3.21-3.33 (5H, m), 3.01 (4H, s),2.29-2.39 (2H, m), 2.15-2.22 (2H, m), 1.83-1.94 (1H, m), 1.57-1.68 (2H,m), 1.22-1.31 (2H, m), 1.17 (3H, d).

Example 2574-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 175F byreplacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 253F and EXAMPLE 7A.¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 8.79 (t, 1H), 8.57 (d, 1H),7.80 (dd, 1H), 7.51 (d, 1H), 7.37-7.44 (m, 2H), 7.34 (d, 2H), 7.15 (d,1H), 7.06 (d, 1H), 7.01 (d, 2H), 6.85 (dd, 1H), 6.63 (dd, 1H), 6.39 (s,1H), 6.13 (d, 1H), 3.60 (t, 4H), 3.43 (q, 2H), 3.01 (s, 4H), 2.63 (d,1H), 2.33-2.47 (m, 6H), 2.22 (d, 4H), 1.94-2.15 (m, 3H), 1.75-1.86 (m,3H), 1.32-1.40 (m, 2H), 1.00 (d, 3H), 0.91 (s, 3H), 0.90 (s, 3H).

Example 2584-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 175F byreplacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 253F and EXAMPLE173C. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.12 (s, 1H), 8.53 (d,1H), 8.19 (d, 1H), 7.79 (dd, 1H), 7.52 (d, 1H), 7.32-7.40 (m, 4H),6.99-7.12 (m, 4H), 6.81 (dd, 1H), 6.60 (dd, 1H), 6.37 (s, 1H), 6.13 (d,1H), 3.92 (dd, 2H), 3.72 (s, 1H), 3.26-3.31 (m, 2H), 2.98 (s, 6H), 2.77(s, 1H), 2.54-2.66 (m, 3H), 2.15-2.30 (m, 4H), 1.94-2.14 (m, 5H),1.73-1.87 (m, 3H), 1.57-1.68 (m, 2H), 1.44-1.54 (m, 2H), 1.31-1.40 (m,2H), 1.00 (d, 3H), 0.91 (d, 2H).

Example 2594-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamideExample 259A 4-(cyclohexylmethylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting cyclohexylmethylamine for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 259B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 259A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.10 (s, 1H),8.53 (m, 1H), 8.52 (d, 1H), 7.72 (dd, 1H), 7.44 (d, 1H), 7.32, (d, 1H),7.31 (dd, 1H), 7.26 (d, 2H), 7.08 (d, 1H), 6.99 (d, 1H), 6.96 (d, 2H),6.80 (dd, 1H), 6.58 (dd, 1H), 6.32 (s, 1H), 6.07 (d, 1H), 3.18 (t, 2H),2.96 (br m, 4H), 2.65 (d, 2H), 2.06 (br m, 6H), 1.87 (s, 2H), 1.63 (m,4H), 1.56 (m, 2H), 1.30 (t, 2H), 1.11 (m, 2H), 0.91 (m, 3H), 0.85 (s,6H).

Example 2604-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamideExample 260A 4-(morpholinoamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting morpholin-4-amine for1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A.

Example 260B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 260A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz, pyridine-d5)δ 9.28 (s, 1H), 9.25 (d, 1H), 8.39 (dd, 1H), 8.18 (d, 1H), 7.66 (d, 1H),7.52-7.56 (m, 2H), 7.40-7.46 (m, 3H), 7.09 (dd, 1H), 7.06 (d, 2H), 6.73(dd, 1H), 6.60 (s, 1H), 6.54 (d, 1H), 3.87 (s, 2H), 3.74 (d, 2H),3.00-3.08 (m, 4H), 2.89 (d, 4H), 2.76 (s, 2H), 2.24 (t, 2H), 2.08-2.15(m, 4H), 1.97 (s, 2H), 1.38 (t, 2H), 0.93 (s, 6H).

Example 2614-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-3-ylmethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 175F byreplacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 26C and EXAMPLE 180A,respectively. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 2H),8.45-8.70 (m, 2H), 7.80 (dd, 1H), 7.51 (d, 1H), 7.38-7.42 (m, 2H), 7.33(d, 2H), 7.16 (d, 1H), 7.07 (d, 1H), 7.03 (d, 2H), 6.86 (dd, 1H), 6.65(dd, 1H), 6.39 (s, 1H), 6.14 (d, 1H), 3.79 (dd, 1H), 3.68-3.75 (m, 1H),3.23-3.38 (m, 3H), 3.18 (dd, 1H), 3.03 (s, 4H), 2.72 (s, 2H), 2.07-2.21(m, 6H), 1.79-1.96 (m, 4H), 1.57-1.64 (m, 1H), 1.41-1.51 (m, 1H), 1.37(t, 2H), 1.22-1.33 (m, 1H), 0.92 (s, 6H).

Example 2624-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 1E andEXAMPLE 260A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz, pyridine-d5)δ 12.45 (s, 1H), 9.26 (s, 1H), 9.17 (d, 1H), 8.27 (dd, 1H), 8.17 (d,1H), 7.61 (d, 1H), 7.48 (t, 1H), 7.45 (d, 2H), 7.39 (d, 1H), 7.05-7.13(m, 3H), 6.71-6.81 (m, 3H), 6.67 (d, J=2.1 Hz, 1H), 3.87 (s, 2H),3.61-3.78 (m, 2H), 2.99-3.08 (m, 4H), 2.89 (d, 4H), 2.76 (s, 2H), 2.25(t, 2H), 2.08-2.16 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 2634-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide

This example was prepared by substituting tetrahydro-2H-pyran-4-amine,hydrochloric acid for (3S,4R)-4-amino-1-benzylpiperidin-3-ol,hydrochloric acid in EXAMPLE 187B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.15 (s, 2H), 8.57 (d, 1H), 8.24 (d, 1H), 7.78(dd, 1H), 7.49 (d, 1H), 7.37-7.40 (m, 3H), 7.32 (d, 2H), 7.12-7.16 (m,2H), 7.22 (d, 2H), 6.84 (dd, 1H), 6.64 (dd, 1H), 6.37 (s, 1H), 6.13 (d,1H), 3.85-3.87 (m, 2H), 3.45 (t, 2H), 3.02 (s, 4H), 2.71 (s, 2H),2.11-2.16 (m, 7H), 1.87-1.93 (m, 4H), 1.58-1.62 (m, 2H), 1.36 (t, 2H),0.90 (s, 6H).

Example 2644-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(3-methyloxetan-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting(3-methyloxetan-3-yl)methanamine for(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in EXAMPLE187B. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.14 (s, 2H), 8.67 (t,1H), 8.58 (d, 1H), 7.81 (dd, 1H), 7.49 (d, 1H), 7.36-7.39 (m, 2H), 7.32(d, 2H), 7.12-7.14 (m, 2H), 7.02 (d, 2H), 6.84 (dd, 1H), 6.63 (dd, 1H),6.37 (s, 1H), 6.13 (d, 1H), 4.44 (d, 2H), 4.30 (d, 2H), 3.55 (d, 2H),3.01 (s, 4H), 2.70 (s, 2H), 2.11-2.15 (m, 7H), 1.93 (s 3H), 1.36 (t,2H), 0.90 (s, 6H).

Example 2654-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methoxycyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting 4-methoxycyclohexanamine for(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in EXAMPLE187B. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.16 (s, 2H), 8.83 (d,1H), 8.30 (d, 1H), 7.79 (dd, 1H), 7.50 (d, 1H), 7.37-7.41 (m, 2H), 7.33(d, 2H), 7.10-7.14 (m, 2H), 7.03 (d, 2H), 6.85 (dd, 1H), 6.65 (dd, 1H),6.39 (s, 1H), 6.14 (d, 1H), 3.24-3.25 (m, 5H), 3.03 (s, 4H), 2.72 (s,2H), 2.14-2.17 (m, 8H), 1.92 (m, 3H), 1.63-1.65 (m, 2H), 1.38 (t, 2H),0.92 (s, 6H).

Example 2664-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(1,1-dioxidothiomorpholin-4-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 187A for4-chloro-3-nitrobenzene sulfonamide and4-(3-aminopropyl)thiomorpholine-1,1-dioxide for1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A. ¹H NMR (400MHz, dimethylsulfoxide-d₆) δ 11.16 (s, 1H), 8.86 (t, 1H), 8.58 (d, 1H),7.82 (dd, 1H), 7.50 (t, 1H), 7.40 (m, 2H), 7.33 (d, 2H), 7.15 (m, 1H),7.04 (m, 3H), 6.85 (dd, 1H), 6.64 (m, 1H), 6.38 (m, 1H), 6.13 (m, 1H),3.43 (m, 2H), 3.12 (m, 4H), 3.01 (m, 4H), 2.89 (m, 4H), 2.72 (m, 2H),2.57 (t, 2H), 2.16 (m, 6H), 1.94 (m, 2H), 1.78 (t, 2H), 1.37 (t, 2H),0.93 (s, 6H).

Example 2674-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxopiperidin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 187A for4-chloro-3-nitrobenzene sulfonamide and 1-(2-aminoethyl)piperidine-2-onefor 1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A. ¹H NMR (400MHz, dimethylsulfoxide-d₆) δ 11.12 (s, 1H), 8.61 (m, 1H), 8.52 (m, 1H),7.78 (d, 1H), 7.51 (d, 1H), 7.37 (m, 2H), 7.33 (d, 2H), 7.10 (m, 2H),7.04 (d, 2H), 6.81 (m, 1H), 6.61 (d, 1H), 6.37 (s, 1H), 6.13 (d, 1H),3.52 (m, 4H), 3.28 (t, 2H), 3.00 (m, 4H), 2.71 (m, 2H), 2.17 (m, 8H),1.94 (m, 2H), 1.63 (m, 4H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 2684-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxoimidazolidin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 187A for4-chloro-3-nitrobenzene sulfonamide and 1-(2-aminoethyl)-2-imidazolidonefor 1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A. ¹H NMR (400MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 1H), 8.60 (t, 1H), 8.56 (d, 1H),7.81 (dd, 1H), 7.50 (m, 1H), 7.39 (m, 2H), 7.33 (d, 2H), 7.15 (m, 1H),7.08 (d, 1H), 7.02 (d, 2H), 6.85 (dd, 1H), 6.65 (m, 1H), 6.39 (m, 2H),6.15 (m, 1H), 3.51 (m, 2H), 3.39 (t, 2H), 3.30 (m, 2H), 3.21 (t, 2H),3.03 (m, 4H), 2.72 (m, 2H), 2.14 (m, 6H), 1.93 (m, 2H), 1.37 (t, 2H),0.92 (s, 6H).

Example 2694-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2-pyridin-4-ylethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting 4-(2-aminoethyl)pyridine for1-(2-methoxyethyl)-piperidin-4-ylamine and EXAMPLE 187A for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A, except the materialwas purified by preparative HPLC on a Phenomenex Luna C8(2) 5 um 100 ÅAXIA column (30 mm×75 mm). A gradient of acetonitrile and 0.1%trifluoroacetic acid in water was used, at a flow rate of 50 mL/minute(0-0.5 minutes 10% acetonitrile, 0.5-6.0 minutes linear gradient 10-100%acetonitrile, 6.0-7.0 minutes 100% acetonitrile, 7.0-8.0 minutes lineargradient 100-10% acetonitrile) to isolate the title compound as the bistrifluoroacetic acid salt. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ11.45 (br s, 1H), 11.18 (br s, 1H), 8.77 (d, 2H), 8.61 (t, 1H), 8.60 (d,1H), 7.86 (dd, 1H), 7.84 (d, 2H), 7.54 (d, 1H), 7.43-7.37 (m, 4H), 7.22(d, 1H), 7.15 (d, 1H), 7.08 (d, 2H), 6.85 (dd, 1H), 6.70 (dd, 1H), 6.38(t, 1H), 6.22 (d, 1H), 3.77 (q, 2H), 3.68-3.54 (m, 4H), 3.27 (m, 2H),3.16 (t, 2H), 3.00 (m, 2H), 2.74 (m, 2H), 2.18 (m, 2H), 2.01 (d, 2H),1.45 (t, 2H), 0.94 (s, 6H).

Example 2704-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-morpholin-4-yl-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 187A for4-chloro-3-nitrobenzenesulfonamide and morpholine for1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A, except thecrude material was purified by preparative HPLC using a C18 column,250×50 mm, 10μ, and eluting with a gradient of 20-100% CH₃CN vs. 0.1%trifluoroacetic acid in water, giving the title compound as atrifluoroacetate salt. The salt was dissolved in dichloromethane (6 mL)and was washed with 50% aqueous NaHCO₃. The organic layer was dried overanhydrous Na₂SO₄, filtered, and concentrated to give the title compound.¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 1H), 8.31 (d, 1H),7.87 (dd, 1H), 7.53 (d, 1H), 7.41 (m, 2H), 7.33 (d, 2H), 7.24 (d, 1H),7.16 (s, 1H), 7.02 (d, 2H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.40 (s, 1H),6.14 (s, 1H), 3.69 (t, 4H), 3.13 (t, 4H), 3.03 (br s, 4H), 2.75 (s, 2H),2.19 (br s, 4H), 2.14 (br t, 2H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s,6H).

Example 2714-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(4-methoxypiperidin-1-yl)-3-nitrophenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 187A for4-chloro-3-nitrobenzenesulfonamide and 4-methoxy-piperidine for1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A, except thecrude material was purified by preparative HPLC using a C18 column,250×50 mm, 10μ, and eluting with a gradient of 20-100% CH₃CN vs. 0.1%trifluoroacetic acid in water, giving the product as a trifluoroacetatesalt. The salt was dissolved in dichloromethane (6 mL) and washed with50% aqueous NaHCO₃. The organic layer was dried over anhydrous Na₂SO₄,filtered, and concentrated to give the title compound. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.17 (s, 1H), 8.28 (d, 1H), 7.81 (dd, 1H), 7.53(d, 1H), 7.41 (m, 2H), 7.33 (d, 2H), 7.22 (d, 1H), 7.16 (s, 1H), 7.04(d, 2H), 6.86 (dd, 1H), 6.64 (dd, 1H), 6.40 (s, 1H), 6.14 (s, 1H), 3.42(m, 1H), 3.27 (s, 3H), 3.25 (m, 2H), 3.00 (m, 6H), 2.73 (s, 2H), 2.18(br s, 4H), 2.13 (br t, 2H), 1.94 (s, 2H), 1.91 (m, 2H), 1.56 (m, 2H),1.38 (t, 2H), 0.92 (s, 6H).

Example 2724-(4-{[2-(4-chlorophenyl)-5-pyrrolidin-1-ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting pyrrolidine for morpholine inEXAMPLE 249G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.04 (s, 1H),8.44 (d, 1H), 8.42 (m, 1H), 7.70 (dd, 1H), 7.55 (d, 1H), 7.37 (d, 2H),7.32 (m, 2H), 7.09 (d, 2H), 7.00 (d, 1H), 6.89 (d, 1H), 6.76 (d, 1H),6.54 (d, 1H), 6.32 (d, 1H), 6.13 (d, 1H), 3.83 (m, 3H), 3.06 (m, 15H),2.23 (m, 6H), 1.84 (m, 6H), 1.62 (m, 4H), 1.24 (m, 3H).

Example 2734-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(3-oxopiperazin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamideExample 273A3-nitro-4-[2-(3-oxo-piperazin-1-yl)-ethylamino]-benzenesulfonamide

4-(2-Amino-ethyl)-piperazin-2-one (5.51 g) and triethylamine (9.07 mL,6.59 g) were added to 1,4-dioxane (100 mL), N,N-dimethylacetamide (20mL), and water (10 mL) and mixed until dissolved.4-Chloro-3-nitrobenzenesulfonamide (7.00 g) was added, and the mixturewas heated to 90° C. for 16 hours. The mixture was cooled and thesolvent was removed under vacuum. The crude material was purified byrecrystallization from 20% methanol in dichloromethane with subsequentwashing of the recrystallized solid with 10% methanol in dichloromethanefollowed by washing with 100% dichloromethane.

Example 273B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(3-oxopiperazin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 273A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.15 (br s, 1H), 8.73 (t, 1H), 8.58 (d, 1H),7.82 (dd, 1H), 7.76 (br s, 1H), 7.51 (d, 1H), 7.42-7.38 (m, 2H), 7.34(d, 2H), 7.16 (d, 1H), 7.06-7.01 (m, 3H), 6.85 (dd, 1H), 6.65 (dd, 1H),6.38 (t, 1H), 6.15 (d, 1H), 3.48 (q, 2H), 3.17 (m, 2H), 3.04 (m, 6H),2.72 (br s, 2H), 2.70-2.62 (m, 2H), 2.16 (m, 8H), 1.95 (br s, 2H), 1.38(t, 2H), 0.92 (s, 6H).

Example 2744-[4-({4′-chloro-4-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 125D for EXAMPLE 26Cand EXAMPLE 174A for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.62 (s, 1H), 11.33 (s, 1H), 9.55 (d, 1H), 8.49(d, 1H), 7.74 (dd, 1H), 7.55 (m, 5H), 7.35 (m, 2H), 7.30 (m, 1H), 7.19(dd, 2H), 6.96 (m, 2H), 6.73 (dd, 1H), 6.40 (m, 1H), 6.33 (m, 1H), 6.24(s, 1H), 4.37 (m, 2H), 3.53 (m, 8H), 3.30 (m, 8H), 3.23 (m, 4H), 2.90(s, 6H), 2.84 (s, 3H).

Example 2754-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1,1-dioxidotetrahydrothien-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 187A for4-chloro-3-nitrobenzene sulfonamide and(1,1-dioxidotetrahydrothien-3-yl)methylamine hydrochloride for1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A. ¹H NMR (400MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 1H), 8.72 (t, 1H), 8.59 (d, 1H),7.82 (dd, 1H), 7.51 (d, 1H), 7.40 (m, 2H), 7.33 (d, 2H), 7.16 (m, 2H),7.03 (d, 2H), 6.86 (dd, 1H), 6.65 (dd, 1H), 6.40 (m, 1H), 6.14 (d, 1H),3.55 (t, 2H), 3.28 (m, 1H), 3.23 (m, 1H), 3.05 (m, 5H), 2.91 (m, 1H),2.74 (m, 3H), 2.27 (m, 1H), 2.15 (m, 6H), 1.95 (m, 2H), 1.86 (m, 1H),1.38 (t, 2H), 0.91 (s, 6H).

Example 2764-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 187A for4-chloro-3-nitrobenzene sulfonamide and1,1-dioxidotetrahydrothiene-3-ylamine for1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A. ¹H NMR (400MHz, dimethylsulfoxide-d₆) δ 11.20 (bs, 1H), 11.15 (s, 1H), 8.59 (d,1H), 8.50 (d, 1H), 7.86 (dd, 1H), 7.50 (d, 1H), 7.39 (m, 2H), 7.33 (d,2H), 7.19 (d, 1H), 7.14 (m, 1H), 7.03 (d, 2H), 6.85 (dd, 1H), 6.65 (dd,1H), 6.39 (m, 1H), 6.15 (d, 1H), 4.63 (m, 1H), 3.64 (m, 1H), 3.37 (m,2H), 3.20 (m, 1H), 3.03 (m, 4H), 2.73 (m, 2H), 2.57 (m, 1H), 2.28 (m,1H), 2.15 (m, 6H), 1.95 (m, 2H), 1.38 (t, 2H), 0.91 (s, 6H).

Example 2774-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-(trifluoromethyl)phenyl]sulfonyl}benzamideExample 277A4-((tetrahydro-2H-pyran-4-yl)methylamino)-3-(trifluoromethyl)benzenesulfonamide

A mixture of 4-fluoro-3-(trifluoromethyl)benzenesulfonamide (1.056 g),(tetrahydro-2H-pyran-4-yl)methanamine (0.5 g) andN,N-diisopropylethylamine (1.68 g) in anhydrous dimethylsulfoxide (15mL) solution was heated at 90° C. overnight. The reaction mixture wascooled to room temperature and diluted with ethyl acetate. The organicphase was washed with water, brine, dried over anhydrous sodium sulfate,filtered and concentrated to afford the title compound.

Example 277B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-(trifluoromethyl)phenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 277A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.22 (s, 1H),11.20 (s, 1H), 7.91 (d, 1H), 7.76 (dd, 1H), 7.55 (d, 1H), 7.41 (m, 4H),7.20 (m, 1H), 7.08 (d, 2H), 6.88 (m, 2H), 6.70 (dd, 1H), 6.58 (m, 1H),6.42 (m, 1H), 6.19 (m, 1H), 3.83 (m, 2H), 3.56 (m, 4H), 3.25 (m, 4H),3.15 (m, 2H), 2.99 (m, 2H), 2.74 (m, 2H), 2.18 (m, 2H), 2.02 (m, 2H),1.84 (m, 1H), 1.57 (m, 2H), 1.44 (m, 2H), 1.19 (m, 2H), 0.93 (s, 6H).

Example 2784-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[2-(1,3-dioxolan-2-yl)ethyl]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

A mixture of EXAMPLE 187A (0.079 g),dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.016 g), andpalladium acetate (0.0045 g) in tetrahydrofuran (1 mL) was stirred atroom temperature for 5 minutes. To this mixture was added(2-(1,3-dioxolan-2-yl)ethyl)zinc(II) bromide (0.6 mL). The reactionmixture was stirred overnight. The solvent was removed, and the residuewas purified by reverse phase Prep HPLC. The desired fractions werecombined, and the organic solvent was partially removed. The resultingmixture was treated with saturated aqueous NaHCO₃, extracted with ethylacetate, dried over MgSO₄, filtered, and concentrated to give the titlecompound. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.14 (s, 1H), 8.37(s, 1H), 8.00 (s, 1H), 7.55 (br s., 1H), 7.52 (d, 1H), 7.33-7.39 (m,4H), 7.08 (br s, 1H), 7.04 (d, 2H), 6.83 (dd, 1H), 6.62 (d, 1H), 6.38(s, 1H), 6.15 (d, 1H), 4.85 (t, 1H), 3.87-3.89 (m, 2H), 3.76-3.79 (m,2H), 3.04 (s, 4H), 2.91-2.94 (m, 2H), 2.11-2.15 (m, 4H), 1.88-1.91 (s,4H), 1.39 (t, 2H), 0.92 (s, 6H).

Example 2794-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamideExample 279A3-nitro-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide

(Tetrahydro-2H-pyran-4-yl)methanol (2.0 g) in tetrahydrofuran (20 mL)was treated with 60% NaH (1.377 g). The mixture was stirred for 20minutes at the room temperature. To this mixture was added4-fluoro-3-nitrobenzenesulfonamide (2.84 g) portion-wise. The reactionwas stirred for another 2 hours. The mixture was poured into water,neutralized with 10% HCl, and extracted with ethyl acetate three times.The combined organic layers were washed with brine, dried over MgSO₄,filtered, and concentrated. The residue was purified with flash columnchromatography on silica gel eluting with 20%-60% ethyl acetate inhexanes.

Example 279B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 279A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.16 (s, 1H),8.38 (d, 1H), 8.05 (dd, 1H), 7.51 (d, 1H), 7.38-7.41 (m, 3H), 7.34 (d,1H), 7.15 (d, 1H), 7.04 (d, 2H), 6.85 (dd, 1H), 6.65 (dd, 1H), 6.39 (s,1H), 6.15 (d, 1H), 4.08 (d, 2H), 3.88 (dd, 2H), 3.04 (s, 4H), 2.77 (s,2H), 2.12-2.22 (m, 4H), 1.95 (br s, 2H), 1.64 (dd, 2H), 1.36-1.39 (m,2H), 0.92 (s, 6H).

Example 2804-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[2-(3-oxopiperazin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 1E andEXAMPLE 273A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.24 (br s, 1H), 8.72 (t, 1H), 8.51 (d, 1H),7.76 (br s, 1H), 7.72 (dd, 1H), 7.53 (d, 1H), 7.34 (d, 2H), 7.28 (t,1H), 7.18 (d, 1H), 7.04 (d, 2H), 6.97 (t, 2H), 6.70 (dd, 1H), 6.43 (d,1H), 6.28-6.23 (m, 2H), 3.48 (q, 2H), 3.17 (m, 2H), 3.04 (m, 6H), 2.70(br s, 2H), 2.68-2.63 (m, 2H), 2.16 (m, 8H), 1.95 (br s, 2H), 1.38 (t,2H), 0.92 (s, 6H).

Example 2814-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methyl-5-oxopyrrolidin-3-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 187A for4-chloro-3-nitrobenzenesulfonamide and 4-amino-1-methylpyrrolidin-2-onehydrochloride for 1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE189A, except the crude was purified by preparative HPLC using a C18column, 250×50 mm, 10μ, and eluting with a gradient of 20-100% CH₃CN vs.0.1% trifluoroacetic acid in water, giving the product as atrifluoroacetate salt. The salt was dissolved in dichloromethane (6 mL)and washed with 50% aqueous NaHCO₃. The organic layer was dried overanhydrous Na₂SO₄, filtered, and concentrated to give the title compound.¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.14 (s, 1H), 8.56 (d, 1H),8.34 (br d, 1H), 7.82 (dd, 1H), 7.53 (d, 1H), 7.39 (m, 2H), 7.33 (d,2H), 7.11 (s, 1H), 7.04 (m, 3H), 6.83 (dd, 1H), 6.64 (dd, 1H), 6.38 (s,1H), 6.15 (s, 1H), 4.45 (m, 1H), 3.80 (dd, 1H), 3.35 (m, 1H), 3.02 (brs, 4H), 2.81 (dd, 1H), 2.75 (s, 3H), 2.71 (s, 2H), 2.40 (dd, 1H), 2.15(m, 6H), 1.94 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 2824-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methyl-6-oxopiperidin-3-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 187A for4-chloro-3-nitrobenzenesulfonamide and 5-amino-1-methylpiperidin-2-onehydrochloride for 1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE189A, except the crude was purified by preparative HPLC using a C18column, 250×50 mm, 10μ, and eluting with a gradient of 20-100% CH₃CN vs.0.1% trifluoroacetic acid in water, giving the product as atrifluoroacetate salt. The salt was dissolved in dichloromethane (6 mL)and washed with 50% aqueous NaHCO₃. The organic layer was dried overanhydrous Na₂SO₄ and concentrated to give the title compound. ¹H NMR(500 MHz, dimethylsulfoxide-d₆) δ 11.16 (s, 1H), 8.58 (d, 1H), 8.31 (brd, 1H), 7.85 (dd, 1H), 7.53 (d, 1H), 7.39 (m, 2H), 7.33 (d, 2H), 7.25(d, 1H), 7.14 (s, 1H), 7.03 (d, 2H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.39(s, 1H), 6.14 (s, 1H), 4.22 (m, 1H), 3.57 (dd, 1H), 3.02 (br s, 4H),2.84 (m, 1H), 2.83 (s, 3H), 2.72 (s, 2H), 2.36 (m, 2H), 2.16 (m, 6H),2.05 (m, 2H), 1.94 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 2834-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(piperidin-1-ylamino)phenyl]sulfonyl}benzamideExample 283A 3-nitro-4-(piperidin-1-ylamino)benzenesulfonamide

This example was prepared by substituting piperidin-1-amine for(tetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 1F.

Example 283B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(piperidin-1-ylamino)phenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 283A for EXAMPLE 1Fand EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.27 (brs, 1H), 11.33 (s, 1H), 9.14 (s, 1H),8.48 (d, 1H), 7.66 (dd, 1H), 7.52 (t, 2H), 7.34 (d, 2H), 7.29 (t, 1H),7.19 (d, 1H), 7.04 (d, 2H), 6.97 (t, 1H), 6.71 (dd, 1H), 6.41 (d, 1H),6.28 (m, 2H), 3.05 (m, 4H), 2.78 (m, 6H), 2.17 (m, 6H), 1.95 (s, 2H),1.67 (m, 6H), 1.38 (t, 2H), 0.93 (s, 6H).

Example 2844-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(piperidin-1-ylamino)phenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 283A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.28 (s, 1H),11.11 (s, 1H), 9.02 (s, 1H), 8.50 (s, 1H), 7.79 (dd, 1H), 7.52 (m, 2H),7.35 (m, 4H), 7.07 (m, 3H), 6.82 (m, 1H), 6.60 (m, 1H), 6.36 (m, 1H),6.14 (m, 1H), 2.99 (m, 4H), 2.75 (m, 6H), 2.16 (m, 6H), 1.99 (m, 2H),1.94 (m, 2H), 1.64 (m, 4H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 2854-(4-{[4-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 285A 4-(4-chlorophenyl)-1-methyl-1H-pyrazole-5-carbaldehyde

4-Bromo-1-methyl-1H-pyrazole-5-carbaldehyde (0.500 g),4-chlorophenylboronic acid (0.455 g), tetrabutylammonium bromide (0.853g), potassium carbonate (0.914 g) and palladium acetate (0.030 g) werestirred together in 5 mL of water and heated to 45° C. After stirringfor 2.5 hours, the reaction was diluted with ethyl acetate (75 mL) andwashed with water (25 mL), brine (50 mL), dried over magnesium sulfate,filtered and concentrated to give the crude material. The solid waschromatographed over silica gel (SF40-80) eluted using a gradient of 5%to 25% ethyl acetate/hexanes over 30 minutes.

Example 285B methyl2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 285A for4′-chlorobiphenyl-2 carboxaldehyde and methyl2-(1H-indol-5-yloxy)-4-(piperazin-1-yl)benzoate for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 285C2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 285B for EXAMPLE 1D inEXAMPLE 1E.

Example 285D2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide

This example was prepared by substituting EXAMPLE 285C for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (300 MHz, CDCL3) δ 10.30 (s, 1H), 8.85 (d, 1H), 8.50(s, 1H), 8.30 (s, 1H), 8.12 (dd, 1H), 7.95 (d, 1H), 7.49 (s, 1H), 7.43(d, 1H), 7.36-7.22 (m, 6H), 6.97 (dd, 1H), 6.87 (d, 1H), 6.53 (d, 2H),6.08 (s, 1H), 4.08-3.98 (m, 2H), 3.92 (s, 3H), 3.55 (s, 2H), 3.42 (s,2H), 3.33-3.19 (m, 2H), 3.08 (s, 4H), 2.38 (s, 4H), 1.98 (d, 1H), 1.72(s, 2H), 1.52-1.33 (m, 2H).

Example 2864-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methyloxetan-3-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamideExample 286A 4-((3-methyloxetan-3-yl)methoxy)-3-nitrobenzenesulfonamide

This example was prepared by substituting (3-methyloxetan-3-yl)methanolfor (tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 279A.

Example 286B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methyloxetan-3-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 286A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.08 (s, 1H),8.26 (d, 1H), 8.18 (d, 1H), 7.92 (m, 1H), 7.53 (m, 1H), 7.34 (m, 3H),7.25 (m, 1H), 7.04 (m, 3H), 6.91 (m, 1H), 6.76 (m, 1H), 6.59 (m, 1H),6.35 (m, 1H), 6.15 (d, 1H), 4.47 (d, 1H), 4.29 (d, 1H), 3.40 (m, 2H),3.13 (m, 2H), 2.98 (m, 4H), 2.72 (m, 2H), 2.16 (m, 6H), 1.94 (m, 2H),1.36 (m, 5H), 0.93 (s, 6H).

Example 2874-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(1-oxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}phenyl)sulfonyl]benzamideExample 287A3-nitro-4-((tetrahydro-2H-thiopyran-4-yl)methylamino)benzenesulfonamide

This example was prepared by substituting(tetrahydro-2H-thiopyran-4-yl)methanamine, hydrochloride for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 287B3-nitro-4-((1-oxidotetrahydro-2H-thiopyran-4-yl)methylamino)benzenesulfonamide

EXAMPLE 287A (150 mg) was suspended in methanol (5 mL). The reactionmixture was cooled to 0° C., followed by the addition of Oxone® (220 mg)in water (3 mL). The reaction mixture was stirred at room temperaturefor 2 hours. The precipitate was filtered and washed with Na₂S₂O₃solution and water. The solid was dried in a vacuum oven overnight, andused in the next step without further purification.

Example 287C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(1-oxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}phenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 287B for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 1H),8.69 (t, 1H), 8.58 (d, 1H), 7.81 (dd, 1H), 7.51 (d, 1H), 7.40 (m, 2H),7.33 (d, 2H), 7.15 (m, 2H), 7.03 (d, 2H), 6.86 (dd, 1H), 6.65 (dd, 1H),6.40 (m, 1H), 6.13 (m, 1H), 3.38 (m, 4H), 3.05 (m, 6H), 2.73 (m, 2H),2.11 (m, 8H), 1.95 (m, 3H), 1.67 (m, 2H), 1.38 (t, 2H), 0.90 (s, 6H).

Example 2884-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1,3-thiazol-5-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting thiazol-5-ylmethanamine,hydrochloric acid for (3S,4R)-4-amino-1-benzylpiperidin-3-ol,hydrochloric acid in EXAMPLE 187B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.18 (s, 2H), 9.13 (t, 1H), 8.99 (s, 1H), 8.60(d, 1H), 7.95 (s, 1H), 7.82 (dd, 1H), 7.50 (d, 1H), 7.39-7.42 (, 2H),7.33 (d, 2H), 7.17 (d, 1H), 7.14 (d, 1H), 7.03 (d, 2H), 6.85 (dd, 1H),6.64 (dd, 1H), 6.40 (s, 1H), 6.13 (d, 1H), 4.91 (d, 2H), 3.03 (s, 4H),2.73 (s, 2H), 2.12-2.18 (m, 6H), 1.94 (s, 2H), 1.38 (t, 2H), 0.92 (s,6H).

Example 2894-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 279A for EXAMPLE 1Fand EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.25 (s, 1H), 8.21 (d, J=2.14 Hz, 1H), 7.95(dd, 1H), 7.54 (d, 1H), 7.33-7.38 (m, 3H), 7.28 (t, 1H), 7.17 (d, 1H),7.04 (d, 2H), 6.97 (t, 1H), 6.70 (dd, 1H), 6.41 (d, 1H), 6.27-6.29 (m,2H), 4.08 (d, 2H), 3.88 (dd, 2H), 3.07 (s, 4H), 2.80 (s, 2H), 2.24 (brs, 2H), 2.12-2.16 (m, 2H), 1.96 (s, 2H), 1.65 (dd, 2H), 1.37-1.40 (m,2H), 0.92 (s, 6H).

Example 2904-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 290A 2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enecarbaldehyde

The title compound was prepared as described in EXAMPLE 253B byreplacing EXAMPLE 253A with EXAMPLE 19C.

Example 290B tert-butyl4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazine-1-carboxylate

The title compound was prepared as described in EXAMPLE 1A by replacingEXAMPLE 27C with EXAMPLE 290A.

Example 290C1-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazine

The title compound was prepared as described in EXAMPLE 1B by replacingEXAMPLE 1A with EXAMPLE 290B.

Example 290D ethyl2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

The title compound was prepared as described in EXAMPLE 20D by replacingEXAMPLE 20A and EXAMPLE 20C with EXAMPLE 26A and EXAMPLE 290C,respectively.

Example 290E2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

The title compound was prepared as described in EXAMPLE 1E by replacingEXAMPLE 1D with EXAMPLE 290D.

Example 290F2-(1H-indol-5-yloxy)-4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 175F byreplacing EXAMPLE 175E with EXAMPLE 290E. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.17 (s, 2H), 8.62 (t, 1H), 8.58 (d, 1H), 7.80(dd, 1H), 7.51 (d, 1H), 7.38-7.43 (m, 2H), 7.33 (d, 2H), 7.16 (d, 1H),7.10 (d, 1H), 7.07 (d, 3H), 6.86 (dd, 1H), 6.65 (dd, 1H), 6.39 (s, 1H),6.14 (d, 1H), 3.85 (dd, 2H), 3.23-3.31 (m, 4H), 3.02 (s, 4H), 2.68 (s,2H), 2.17 (d, 6H), 1.85-1.95 (m, 3H), 1.61 (d, 2H), 1.39 (t, 2H),1.20-1.30 (m, 2H), 0.92 (s, 6H).

Example 2914-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2-tetrahydro-2H-pyran-4-ylethyl)amino]phenyl}sulfonyl)benzamideExample 291A3-nitro-4-(2-(tetrahydro-2H-pyran-4-yl)ethylamino)benzenesulfonamide

The title compound was prepared as described in EXAMPLE 1F by replacing(tetrahydropyran-4-yl)methylamine with2-(tetrahydro-2H-pyran-4-yl)ethanamine.

Example 291B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2-tetrahydro-2H-pyran-4-ylethyl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared as described in EXAMPLE 175F byreplacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 26C and EXAMPLE 291A,respectively. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.16 (s, 2H),8.57 (d, 1H), 8.53 (t, 1H), 7.80 (dd, 1H), 7.51 (d, 1H), 7.37-7.42 (m,2H), 7.33 (d, 2H), 7.14 (d, 1H), 7.01-7.05 (m, 3H), 6.85 (dd, 1H), 6.64(dd, 1H), 6.39 (s, 1H), 6.14 (d, 1H), 3.83 (dd, 2H), 3.41 (q, 2H),3.23-3.30 (m, 2H), 3.02 (s, 4H), 2.71 (s, 2H), 2.08-2.21 (m, 6H), 1.94(s, 2H), 1.52-1.67 (m, 5H), 1.37 (t, 2H), 1.14-1.25 (m, 2H), 0.92 (s,6H).

Example 2924-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[2-(trifluoromethoxy)ethyl]amino}phenyl)sulfonyl]benzamideExample 292A3-nitro-4-(2-(trifluoromethoxy)ethylamino)benzenesulfonamide

This example was prepared by substituting piperidin-1-amine for(tetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 1F.

Example 292B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[2-(trifluoromethoxy)ethyl]amino}phenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 292A for EXAMPLE 1Fand EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.07 (s, 1H), 8.36 (m, 2H), 7.72 (dd, 1H), 7.58(d, 1H), 7.34 (d, 2H), 7.19 (m, 1H), 7.05 (m, 3H), 6.91 (m, 2H), 6.59(d, 1H), 6.21 (m, 3H), 4.28 (t, 2H), 3.72 (q, 2H), 2.94 (m, 4H), 2.71(s, 2H), 2.15 (m, 6H), 1.95 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 2934-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]amino}-3-nitrophenyl)sulfonyl]benzamideExample 293A 4-(2-(2-methoxyethoxy)ethylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting 2-(2-methoxyethoxy)ethanaminefor (tetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 1F.

Example 293B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 293A for EXAMPLE 1Fand EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.28 (s, 1H), 11.23 (s, 1H), 8.59 (m, 1H), 8.50(d, 1H), 7.70 (dd, 1H), 7.52 (d, 1H), 7.34 (d, 2H), 7.28 (t, 1H), 7.17(d, 1H), 7.05 (m, 3H), 6.96 (t, 1H), 6.71 (dd, 1H), 6.42 (d, 1H), 6.26(m, 2H), 3.67 (t, 2H), 3.56 (m, 4H), 3.45 (m, 2H), 3.22 (s, 3H), 3.04(m, 4H), 2.74 (s, 2H), 2.16 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.93(s, 6H).

Example 2944-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[3-(methylsulfonyl)propyl]amino}-3-nitrophenyl)sulfonyl]benzamideExample 294A 4-(3-(methylthio)propylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting 3-(methylthio)propan-1-aminefor (tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 294B 4-(3-(methylsulfonyl)propylamino)-3-nitrobenzenesulfonamide

EXAMPLE 294A (150 mg) was suspended in anhydrous dichloromethane (5 mL)and meta-chloroperoxybenzoic acid (848 mg) was added at 0° C. Thereaction mixture was stirred at room temperature overnight. The cloudysuspension was filtered. The solid was washed with aqueous Na₂S₂O₃solution, saturated aqueous NaHCO₃ solution and water. The solid wasdried and used in the next step without further purification.

Example 294C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[3-(methylsulfonyl)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 26Cand EXAMPLE 294B for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.25 (m, 1H), 8.65 (t, 1H), 8.51 (d, 1H), 7.69(dd, 1H), 7.52 (d, 1H), 7.34 (d, 2H), 7.28 (m, 1H), 7.18 (m, 1H), 7.05(m, 3H), 6.97 (m, 1H), 6.70 (dd, 1H), 6.42 (d, 1H), 6.26 (m, 2H), 3.55(m, 2H), 3.23 (t, 2H), 3.05 (t, 4H), 2.98 (s, 3H), 2.76 (m, 2H), 2.18(m, 6H), 2.02 (m, 2H), 1.96 (m, 2H), 1.38 (t, 2H), 0.93 (s, 6H).

Example 2954-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(1,1-dioxidothiomorpholin-4-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 337A for4-chloro-3-nitrobenzene sulfonamide and4-(3-aminopropyl)thiomorpholine-1,1-dioxide for1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A. ¹H NMR (400MHz, dimethylsulfoxide-d₆) δ 11.23 (s, 1H), 8.79 (s, 1H), 8.48 (d, 1H),7.72 (dd, 1H), 7.54 (d, 1H), 7.34 (d, 2H), 7.26 (t, 1H), 7.15 (d, 1H),6.99 (m, 4H), 6.67 (dd, 1H), 6.40 (d, 1H), 6.24 (m, 2H), 3.42 (q, 2H),3.11 (m, 4H), 3.01 (m, 4H), 2.90 (m, 4H), 2.72 (m, 2H), 2.56 (t, 2H),2.16 (m, 6H), 1.95 (m, 2H), 1.78 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 2964-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethyl)phenyl]sulfonyl}benzamideExample 296A (2-(tetrahydro-2H-pyran-4-yl)ethyl)zinc(II) bromide

A 25 mL round bottom flask was dried at 120° C. for 6 hours. It wascooled by a stream of dry N₂. To this flask was charged with zinc (0.508g). The flask was heated at 70° C. under high vacuum for 30 minutes.After back-filling with N₂, iodine (0.033 g) and N,N-dimethylacetamide(5.2 mL) were added, and the resulting mixture was stirred until the redcolor of iodine had faded. Then, 4-(2-bromoethyl)tetrahydro-2H-pyran(1.0 g) was added to the above mixture via a syringe. The reactionmixture was allowed to stir for 12 hours at 70° C. After cooling, thereaction mixture was used directly for next step.

Example 296B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethyl)phenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 296A for(2-(1,3-dioxolan-2-yl)ethyl)zinc(II) bromide in EXAMPLE 278. ¹H NMR (500MHz, dimethylsulfoxide-d₆) δ 11.15 (s, 2H), 8.38 (d, 1H), 8.01 (d, 1H),7.57 (d, 1H), 7.51 (d, 1H), 7.38-7.40 (m, 2H), 7.34 (d, 2H), 7.12 (d,1H), 7.04 (d, 2H), 6.82 (dd, 1H), 6.64 (dd, 1H), 6.38 (s, 1H), 6.16 (d,1H), 3.83 (dd, 2H), 3.24-3.29 (m, 4H), 3.06 (s, 4H), 2.83-2.86 (m, 3H),2.27 (br s, 2H), 2.12-2.14 (m, 4H), 1.96 (s, 2H), 1.95 (s, 2H),1.46-1.62 (m, 6H), 1.37-1.40 (m, 2H), 0.92 (s, 6H).

Example 2974-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamideExample 297A 4-((1,4-dioxan-2-yl)methoxy)-3-nitrobenzenesulfonamide

(1,4-Dioxan-2-yl)methanol (380 mg) in tetrahydrofuran (30 ml) wastreated with sodium hydride (60%) (245 mg) at room temperature for 30minutes. The reaction mixture was cooled in an ice bath and4-fluoro-3-nitrobenzenesulfonamide (675 mg) was added. The resultingmixture was stirred at room temperature for 2 hours and another portionof sodium hydride (60%, 245 mg) was added. The reaction mixture wasstirred overnight and quenched with ice water (3 ml). The cloudy mixturewas filtered and the filtrate was concentrated. The residue wastriturated with methanol to give the title compound.

Example 297B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 175F byreplacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 26C and EXAMPLE 297A,respectively. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.16 (s, 2H),8.39 (d, 1H), 8.06 (dd, 1H), 7.51 (d, 1H), 7.38-7.43 (m, 3H), 7.34 (d,2H), 7.15 (d, 1H), 7.04 (d, 2H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.39 (s,1H), 6.15 (d, 1H), 4.20-4.28 (m, 2H), 3.85-3.91 (m, 1H), 3.82 (dd, 1H),3.74-3.78 (m, 1H), 3.59-3.69 (m, 2H), 3.40-3.51 (m, 2H), 3.05 (s, 4H),2.78 (s, 2H), 2.23 (s, 4H), 2.14 (s, 2H), 1.95 (s, 2H), 1.38 (t, 2H),0.92 (s, 6H).

Example 2984-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 293A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 1H),11.15 (s, 1H), 8.59 (m, 2H), 7.80 (dd, 1H), 7.50 (d, 1H), 7.36 (m, 4H),7.15 (d, 1H), 7.09 (d, 1H), 7.03 (d, 2H), 6.85 (dd, 1H), 6.65 (dd, 1H),6.39 (m, 1H), 6.14 (d, 1H), 3.67 (t, 2H), 3.56 (m, 4H), 3.44 (m, 2H),3.22 (s, 3H), 3.03 (m, 4H), 2.72 (s, 2H), 2.16 (m, 6H), 1.95 (s, 2H),1.38 (t, 2H), 0.92 (s, 6H).

Example 2994-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 337A for4-chloro-3-nitrobenzene sulfonamide and1,1-dioxidotetrahydrothiene-3-ylamine for1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A. ¹H NMR (400MHz, dimethylsulfoxide-d₆) δ 11.35 (s, 1H), 11.23 (s, 1H), 8.49 (m, 2H),7.78 (dd, 1H), 7.52 (d, 1H), 7.34 (d, 2H), 7.27 (m, 1H), 7.16 (m, 2H),7.04 (d, 1H), 6.97 (m, 1H), 6.70 (dd, 1H), 6.42 (d, 1H), 6.26 (m, 2H),4.63 (m, 1H), 3.64 (dd, 1H), 3.37 (m, 2H), 3.20 (m, 1H), 3.05 (m, 4H),2.74 (m, 2H), 2.58 (m, 1H), 2.28 (m, 1H), 2.16 (m, 6H), 1.95 (m, 2H),1.38 (t, 2H), 0.92 (s, 6H).

Example 3004-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(trifluoromethoxy)ethyl]amino}phenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 292A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.17 (m, 2H),8.64 (t, 1H), 8.59 (d, 1H), 7.84 (dd, 1H), 7.51 (d, 1H), 7.40 (m, 2H),7.33 (d, 2H), 7.16 (m, 2H), 7.04 (d, 2H), 6.85 (dd, 1H), 6.64 (dd, 1H),6.39 (m, 1H), 6.14 (d, 1H), 4.31 (t, 2H), 3.78 (q, 2H), 3.04 (m, 4H),2.74 (s, 2H), 2.17 (m, 6H), 1.94 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 3014-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamideExample 301A3-nitro-4-((1-dioxidotetrahydro-2H-thiopyran-4-yl)methylamino)benzenesulfonamide

This example was prepared by substituting EXAMPLE 287A for EXAMPLE 294Ain EXAMPLE 294B.

Example 301B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 26Cand EXAMPLE 301A for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.26 (s, 1H), 8.68 (t, 1H), 8.51 (d, 1H), 7.73(dd, 1H), 7.53 (d, 1H), 7.34 (d, 2H), 7.29 (m, 1H), 7.19 (d, 1H), 7.12(d, 1H), 7.04 (d, 2H), 6.99 (m, 1H), 6.70 (dd, 1H), 6.46 (d, 1H), 6.26(m, 2H), 3.38 (t, 2H), 3.09 (m, 8H), 2.75 (m, 2H), 2.16 (m, 6H), 2.07(m, 2H), 1.95 (m, 3H), 1.70 (m, 2H), 1.38 (t, 2H), 0.91 (s, 6H).

Example 3024-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2,2-difluoroethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamideExample 302A 4-(2,2-difluoroethylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting 2,2-difluoroethanamine for(tetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 1F.

Example 302B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2,2-difluoroethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 302A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.22 (s, 1H),11.05 (s, 1H), 8.46 (m, 2H), 7.76 (m, 1H), 7.53 (d, 1H), 7.33 (m, 4H),7.05 (m, 4H), 6.76 (m, 1H), 6.57 (d, 1H), 6.34 (m, 1H), 6.14 (m, 1H),3.89 (m, 2H), 2.97 (m, 4H), 2.71 (s, 2H), 2.16 (m, 6H), 1.95 (s, 2H),1.38 (t, 2H), 0.92 (s, 6H).

Example 3034-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 26Cand EXAMPLE 163A for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.28 (m, 1H), 8.13 (d, 1H), 7.78 (dd, 1H), 7.52(d, 1H), 7.34 (d, 2H), 7.29 (m, 2H), 7.20 (d, 1H), 7.01 (m, 4H), 6.70(dd, 1H), 6.45 (d, 1H), 6.27 (m, 2H), 3.85 (dd, 2H), 3.26 (t, 4H), 3.05(m, 4H), 2.75 (m, 2H), 2.16 (m, 6H), 1.95 (m, 2H), 1.84 (m, 1H), 1.55(m, 2H), 1.38 (t, 2H), 1.23 (m, 2H), 0.92 (s, 6H).

Example 3044-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 163A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.46 (s, 1H),11.20 (s, 1H), 9.23 (s, 1H), 8.19 (d, 1H), 7.90 (dd, 1H), 7.53 (d, 1H),7.41 (m, 4H), 7.33 (m, 1H), 7.17 (d, 1H), 6.86 (dd, 1H), 6.70 (dd, 1H),6.41 (m, 1H), 6.21 (d, 1H), 3.84 (dd, 2H), 3.57 (m, 4H), 3.26 (m, 6H),3.00 (m, 2H), 2.74 (s, 2H), 2.18 (s, 2H), 2.01 (s, 2H), 1.83 (m, 1H),1.54 (m, 2H), 1.45 (t, 2H), 1.23 (m, 2H), 0.94 (s, 6H).

Example 3054-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4,4-difluorocyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting 4,4-difluorocyclohexanamine,hydrochloric Acid for (3S,4R)-4-amino-1-benzylpiperidin-3-ol,hydrochloric acid in EXAMPLE 187B. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.16 (s, 2H), 8.59 (d, 1H), 8.25 (d, 1H), 7.84(dd, 1H), 7.50 (d, 2H), 7.39-7.41 (m, 2H), 7.33 (d, 2H), 7.15-7.18 (m,2H), 7.03 (d, 2H), 6.85 (dd, 1H), 6.65 (dd, 1H), 6.39 (s, 1H), 6.14 (d,1H), 3.86 (d, 1H), 3.04 (s, 4H), 2.74 (s, 2H), 1.95-2.18 (m, 14H),1.69-1.73 (m, 2H), 1.38 (d, 2H), 0.92 (s, 6H).

Example 3064-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamideExample 306A 1,6-dioxaspiro[2.5]octane-2-carbonitrile

A mixture of dihydro-2H-pyran-4(3H)-one (10.0 g) and2-chloroacetonitrile (7.55 g) in tert-butanol (10 mL) was treated with1.0 N potassium tert-butoxide (100 mL) drop-wise over 20 minutes. Thereaction mixture was stirred at room temperature for 16 hours. It wasdiluted with water (10 mL) and 10% HCl (20 mL). The reaction mixture wasconcentrated to one-third of its original volume, and extracted withdiethyl ether four times. The combined organic layers were washed withbrine, dried over MgSO₄, filtered, and concentrated. The residue waspurified with flash column chromatography on silica gel eluting with20-40% ethyl acetate in hexanes to give the title compound.

Example 306B 2-(4-fluorotetrahydro-2H-pyran-4-yl)-2-hydroxyacetonitrile

EXAMPLE 306A (11.5 g) was dissolved in dichloromethane (40 mL) in apolypropylene bottle. The bottle was cooled to 0° C. To this mixture wasadded 70% hydrogen fluoride-pyridine (10.31 mL) slowly. The mixture wasallowed to warm to room temperature over 3 hours, and stirred for 24hours. The reaction mixture was diluted with ethyl acetate (200 mL) andpoured into saturated aqueous NaHCO₃. Additional solid NaHCO₃ was usedto neutralize the mixture carefully until bubbling ceased. The organiclayer was isolated, and the aqueous layer was extracted with additionalethyl acetate three times (150 mL each). The combined organic layerswere washed with 1% HCl, brine, dried (MgSO₄), filtered and concentratedto give the desired compound which was used directly in the nextreaction.

Example 306C (4-fluorotetrahydro-2H-pyran-4-yl)methanol

EXAMPLE 306B (11.78 g) in 2-propanol (150 mL) and water (37.5 mL) wascooled to 0° C. To this mixture was added sodium borohydride (4.2 g).The mixture was stirred and allowed to warm to room temperature over 3hours. The reaction was quenched with acetone, and stirred for another 1hour. The clear liquid was separated from solid by decanting. Additionalethyl acetate was used to wash the solid, and was decanted. The combinedorganic solution was concentrated. The residue was purified with flashcolumn chromatography on silica gel eluting with 20-40% ethyl acetate inhexanes to give the title compound.

Example 306D4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrobenzenesulfonamide

This example was prepared by substituting EXAMPLE 306C for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 279A.

Example 306E4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 306D for EXAMPLE 1Fand EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.24 (s, 1H), 8.28 (d, 1H), 7.98 (dd, 1H), 7.54(d, 1H), 7.42 (d, 1H), 7.34 (d, 2H), 7.28 (t, 1H), 7.17 (d, 1H), 7.04(d, 2H), 6.97 (t, 1H), 6.70 (dd, 1H), 6.41 (d, 1H), 6.26-6.28 (m, 2H),4.38 (d, 2H), 3.76-3.80 (m, 2H), 3.57-3.62 (m, 2H), 3.06 (s, 4H), 2.80(s, 2H), 2.24 (br s, 2H), 2.15-2.25 (m, 2H), 1.96 (s, 2H), 1.82-1.89 (m,4H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 3074-(4-{[4-(4-chlorophenyl)-1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 307A 4-(4-chlorophenyl)-2-fluoro-5-methylpyridine

A mixture of 2-fluoro-4-iodo-5-methylpyridine (1.9 g),4-chlorophenylboronic acid (1.504 g),tetrakis(triphenylphosphine)palladium(0) (0.463 g), and sodium carbonate(2.55 g) in ethanol (20 mL), water (10 mL) and toluene (10 mL) washeated under reflux for 6 hours. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was separated, andthe aqueous layers were extracted with additional ethyl acetate threetimes. The combined organic layers were washed with brine, dried overMgSO₄, filtered, and concentrated. The residue was purified with flashcolumn chromatography on silica gel using 5% ethyl acetate in hexanes togive the title compound.

Example 307B 5-(bromomethyl)-4-(4-chlorophenyl)-2-fluoropyridine

A mixture of EXAMPLE 307A (1.2 g), N-bromosuccinimide (1.06 g) and AIBN(azobisisobutyronitrile) (0.178 g) in CCl₄ (30 mL) was heated underreflux for 6 hours. After cooling, the solid was filtered off. Thefiltrate was concentrated and loaded onto a silica gel column elutingwith 3% ethyl acetate in hexanes to give the title compound.

Example 307C tert-butyl4-((4-(4-chlorophenyl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate

A mixture of EXAMPLE 307B (1.24 g), tert-butyl piperazine-1-carboxylate(0.768 g), and potassium carbonate (0.570) in N,N-dimethylformamide (20mL) was stirred at room temperature for 2 hours. The reaction mixturewas partitioned between ethyl acetate and water. The organic layer wasseparated, and the aqueous layer was extracted with additional ethylacetate three times. The combined organic layers were washed with brine,dried over MgSO₄, filtered, and concentrated. The residue was purifiedwith flash column chromatography on silica gel using 10% ethyl acetatein hexanes to give the title compound.

Example 307D tert-butyl4-((4-(4-chlorophenyl)-6-oxo-1,6-dihydropyridin-3-yl)methyl)piperazine-1-carboxylate

A mixture of EXAMPLE 307C (1.6 g) and 5% HCl (20 mL) in tetrahydrofuran(20 mL) was heated at 80° C. overnight. The solvent was removed todryness. This solid was re-dissolved and added to tetrahydrofuran (50mL). To this mixture were added BOC₂O (di-t-butyl-dicarbonate) (1.118g), triethylamine (0.72 mL), and 4-dimethylamionpyridine (1.4 g). Thesolvent was removed, and the residue was partitioned between water andethyl acetate. The reaction mixture was stirred overnight. The organiclayers were dried (MgSO₄), filtered, and concentrated. The residue waspurified by Prep HPLC eluting with 20-100% acetonitrile/water with 0.1%trifluoroacetic acid to give the title compound.

Example 307E tert-butyl4-((4-(4-chlorophenyl)-1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)methyl)piperazine-1-carboxylate

EXAMPLE 307D (0.404 g) in N,N-dimethylformamide (5 mL) was treated with60% sodium hydride (0.24 g) at room temperature. To this mixture wasadded 2-iodopropane (0.204 g). The mixture was stirred overnight. Thereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was separated, and the aqueous layers were extracted withadditional ethyl acetate three times. The combined organic layers werewashed with brine, dried over MgSO₄, filtered, and concentrated. Theresidue was purified with flash column chromatography on silica gelusing 10% ethyl acetate in hexanes to give EXAMPLE 307E and EXAMPLE307F.

Example 307F tert-butyl4-((4-(4-chlorophenyl)-6-isopropoxypyridin-3-yl)methyl)piperazine-1-carboxylate

This compound was isolated as a by-product during the preparation ofEXAMPLE 307E.

Example 307G4-(4-chlorophenyl)-1-isopropyl-5-(piperazin-1-ylmethyl)pyridin-2(1H)-one

This example was prepared by substituting EXAMPLE 307E for EXAMPLE 1A inEXAMPLE 1B.

Example 307H ethyl2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 307G for EXAMPLE 20Cand EXAMPLE 26A for EXAMPLE 20A in EXAMPLE 20D.

Example 307I2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 307H for EXAMPLE 1D inEXAMPLE 1E.

Example 307J4-(4-{[4-(4-chlorophenyl)-1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 3071 for EXAMPLE 26Cin EXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.07 (s, 1H),8.62 (t, 1H), 8.59 (d, 1H), 7.79 (dd, 1H), 7.59 (s, 1H), 7.52-7.53 (m, J3H), 7.38-7.45 (m, 4H), 7.15 (d, 1H), 7.10 (d, 1H), 6.87 (dd, 1H), 6.68(dd, 1H), 6.39 (s, 1H), 6.22 (s, 1H), 6.17 (d, 1H), 5.01-5.06 (m, 1H),3.85 (dd, 2H), 3.24-3.31 (m, 6H), 3.09 (s, 2H), 3.00 (s, 4H), 2.26 (m,4H), 2.09 (m, 2H), 1.60-1.63 (m, 2H), 1.30 (d, 6H).

Example 3084-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}phenyl)sulfonyl]benzamideExample 308A 4-sulfamoyl-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide

4-Sulfamoylbenzoic acid (201 mg), (tetrahydro-2H-pyran-4-yl)methanamine(144 mg), 1-hydroxybenzotriazole hydrate (230 mg), and1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (288 mg)were combined in acetonitrile. The mixture was stirred at roomtemperature overnight. The solids were filtered off and reaction mixturewas concentrated. The crude material was purified by flashchromatography eluting with a gradient of 2% methanol/dichloromethane to10% methanol/dichloromethane.

Example 308B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}phenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 308A for EXAMPLE 1Fand EXAMPLE 26C for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.19 (s, 1H), 8.57 (t, 1H), 7.94 (m, 4H), 7.48(d, 1H), 7.43 (d, 1H), 7.40 (t, 1H), 7.33 (d, 2H), 7.21 (d, 1H), 7.03(d, 2H), 6.88 (dd, 1H), 6.63 (dd, 1H), 6.42 (t, 1H), 6.13 (d, 1H), 3.84(dd, 2H), 3.26 (m, 2H), 3.16 (t, 2H), 3.03 (br s, 4H), 2.74 (br s, 2H),2.15 (m, 6H), 1.95 (s, 2H), 1.79 (m, 1H), 1.59 (d, 2H), 1.38 (t, 2H),1.19 (m, 2H), 0.92 (s, 6H).

Example 3094-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamideExample 309A4-(2-methoxyethylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

This example was prepared by substituting EXAMPLE 159C for4-fluoro-3-nitrobenzenesulfonamide and 2-methoxyethylamine for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 309B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 26Cand EXAMPLE 309A for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.26 (s, 1H), 8.13 (d, 1H), 7.79 (dd, 1H), 7.51(d, 1H), 7.34 (d, 2H), 7.29 (t, 1H), 7.24 (m, 1H), 7.19 (d, 1H), 7.04(d, 2H), 6.99 (m, 3H), 6.70 (dd, 1H), 6.44 (d, 1H), 6.27 (m, 2H), 3.52(m, 4H), 3.28 (s, 3H), 3.05 (m, 4H), 2.75 (s, 2H), 2.17 (m, 6H), 1.95(s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 310Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamideExample 310A 4-(aminomethyl)cyclohexanol

The title compound was prepared as described in EXAMPLE 311A byreplacing (4-methoxyphenyl)methanamine with(4-hydroxyphenyl)methanamine.

Example 310B2-(1H-indol-5-yloxy)-N-(4-chloro-3-nitrophenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzamide

The title compound was prepared as described in EXAMPLE 1G by replacingEXAMPLE 1E and EXAMPLE 1F with EXAMPLE 26C and4-chloro-3-nitrobenzenesulfonamide.

Example 310CTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

A mixture of EXAMPLE 310B (100 mg), triethylamine (0.2 ml) and EXAMPLE310A (35 mg) in dioxane (5 ml) was heated at 100° C. for 20 hours andconcentrated. The residue was purified by RP-HPLC (10-70% acetonitrilein 0.1% trifluoroacetic acid water/70 minutes) to provide the titlecompound as a trifluoroacetic acid salt. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.40 (s, 1H), 11.18 (s, 1H), 9.20 (s, 1H), 8.60(t, 1H), 8.58 (d, 1H), 7.77 (dd, 1H), 7.54 (d, 1H), 7.42 (s, 1H),7.37-7.41 (m, 3H), 7.14 (d, 1H), 7.04-7.09 (m, 3H), 6.86 (dd, 1H), 6.69(dd, 1H), 6.39 (s, 1H), 6.21 (s, 1H), 3.50-3.68 (m, 3H), 3.20-3.27 (m,3H), 2.93-3.07 (m, 2H), 2.66-2.82 (m, 2H), 2.13-2.22 (m, 2H), 2.01 (s,2H), 1.83 (d, 2H), 1.67-1.77 (m, 3H), 1.50-1.60 (m, 1H), 1.44 (s, 2H),0.96-1.17 (m, 4H), 0.94 (s, 6H).

Example 311Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamideExample 311A (4-methoxycyclohexyl)methanamine

(4-Methoxyphenyl)methanamine (1 g) in ethanol (10 ml) was treated with5% dry Rh-Al₂O₃ (0.5 g) under H₂ (500 psi) at 60° C. for 6 hours andthen at 125° C. for 26 hours. The insoluble material was filtered offand the filtrate was concentrated to provide the title compound.

Example 311B4-(((Trans-4-methoxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide

4-fluoro-3-nitrobenzenesulfonamide (15 g) and EXAMPLE 311A (11.71 g) intetrahydrofuran (200 ml) was treated with triethylamine (28.5 ml)overnight. The reaction was concentrated and the residue was loaded ontoa C18 column, and eluted with 40-55% acetonitrile in water to providethe title compound.

Example 311C4-(((Cis-4-methoxycyclohexyl)methylamino)-3-nitrobenzenesulfonamide

This compound was made from the same procedure that also producedEXAMPLE 311B.

Example 311DTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared as described in EXAMPLE 175F byreplacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 26C and EXAMPLE 311B,respectively. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 2H),8.55-8.62 (m, 2H), 7.78 (dd, 1H), 7.51 (d, 1H), 7.37-7.43 (m, 2H), 7.33(d, 2H), 7.15 (d, 1H), 7.01-7.08 (m, 3H), 6.86 (dd, 1H), 6.65 (dd, 1H),6.39 (s, 1H), 6.14 (d, 1H), 3.25 (t, 2H), 3.22 (s, 3H), 3.00-3.10 (m,5H), 2.72 (s, 2H), 2.15 (d, 6H), 2.00 (d, 2H), 1.94 (s, 2H), 1.78 (d,2H), 1.53-1.65 (m, 1H), 1.38 (t, 2H), 0.96-1.12 (m, 4H), 0.92 (s, 6H).

Example 312Cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

The title compound (trifluoroacetic acid salt) was obtained during thepurification of EXAMPLE 310C. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ11.39 (s, 1H), 11.18 (s, 1H), 9.17 (s, 1H), 8.61 (t, 1H), 8.58 (d, 1H),7.78 (dd, 1H), 7.54 (d, 1H), 7.34-7.43 (m, 5H), 7.14 (d, 1H), 7.07 (t,3H), 6.85 (dd, 1H), 6.69 (d, 1H), 6.39 (s, 1H), 6.21 (s, 1H), 3.77 (s,1H), 3.58 (s, 2H), 3.24-3.29 (m, 2H), 2.91-3.07 (m, 2H), 2.60-2.81 (m,2H), 2.17 (s, 2H), 2.00 (s, 2H), 1.57-1.72 (m, 4H), 1.43 (t, 7H), 0.94(s, 6H).

Example 313Cis-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared as described in EXAMPLE 175F byreplacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 26C and EXAMPLE 311C,respectively. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 2H),8.60 (t, 1H), 8.58 (d, 1H), 7.78 (dd, 1H), 7.51 (d, 1H), 7.37-7.44 (m,2H), 7.33 (d, 2H), 7.16 (d, 1H), 7.07 (d, 1H), 7.03 (d, 2H), 6.86 (dd,1H), 6.65 (dd, 1H), 6.39 (s, 1H), 6.14 (d, 1H), 3.36-3.39 (m, 1H), 3.26(t, 2H), 3.20 (s, 3H), 3.03 (s, 4H), 2.72 (s, 2H), 2.15 (d, 6H), 1.94(s, 2H), 1.81 (dd, 2H), 1.63-1.73 (m, 1H), 1.48 (dd, 2H), 1.23-1.41 (m,6H), 0.92 (s, 6H).

Example 3144-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethoxy)phenyl]sulfonyl}benzamideExample 314A3-nitro-4-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)benzenesulfonamide

This example was prepared by substituting2-(tetrahydro-2H-pyran-4-yl)ethanol for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 279A.

Example 314B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethoxy)phenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 26Cand EXAMPLE 314A for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.25 (s, 1H), 8.25 (d, 1H), 7.95 (dd, 1H), 7.54(d, 1H), 7.39 (d, 1H), 7.34 (d, 2H), 7.29 (m, 1H), 7.17 (m, 1H), 7.04(d, 2H), 6.97 (m, 1H), 6.70 (dd, 1H), 6.41 (d, 1H), 6.28 (m, 2H), 4.26(t, 2H), 3.83 (m, 2H), 3.27 (m, 2H), 3.07 (m, 4H), 2.80 (m, 2H), 2.15(m, 6H), 1.96 (s, 2H), 1.70 (m, 3H), 1.60 (m, 2H), 1.39 (t, 2H), 1.22(m, 2H), 0.93 (s, 6H).

Example 3154-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 309A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 1H),8.18 (d, 1H), 7.92 (dd, 1H), 7.49 (d, 1H), 7.40 (m, 2H), 7.33 (d, 2H),7.26 (m, 1H), 7.17 (d, 1H), 7.04 (m, 3H), 6.86 (dd, 1H), 6.65 (dd, 1H),6.40 (m, 1H), 6.14 (d, 1H), 3.51 (m, 4H), 3.28 (s, 3H), 3.03 (s, 4H),2.74 (m, 2H), 2.16 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 3164-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[3-(methylsulfonyl)propoxy]-3-nitrophenyl}sulfonyl)benzamideExample 316A 4-(3-(methylthio)propoxy)-3-nitrobenzenesulfonamide

This example was prepared by substituting 3-(methylthio)propan-1-ol for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 279A.

Example 316B 4-(3-(methylsulfonyl)propoxy)-3-nitrobenzenesulfonamide

This example was prepared by substituting EXAMPLE 316A for EXAMPLE 294Ain EXAMPLE 294B.

Example 316C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[3-(methylsulfonyl)propoxy]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 26Cand EXAMPLE 316B for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.24 (s, 1H), 8.28 (d, 1H), 7.96 (dd, 1H), 7.54(d, 1H), 7.35 (m, 3H), 7.29 (t, 1H), 7.17 (d, 1H), 7.04 (d, 2H), 6.96(m, 1H), 6.71 (dd, 1H), 6.39 (d, 1H), 6.29 (m, 2H), 4.34 (t, 2H), 3.27(m, 4H), 3.07 (m, 4H), 3.03 (s, 3H), 2.81 (s, 2H), 2.21 (m, 6H), 1.96(s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 3174-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methoxypropyl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 317A 4-(3-methoxypropylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting 3-methoxypropan-1-amine for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 317B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methoxypropyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 317A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz, pyridine-d5)δ 12.24 (s, 1H), 9.30 (d, 1H), 8.88 (t, 1H), 8.28 (dd, 1H), 8.19 (d,1H), 7.51-7.56 (m, 2H), 7.41-7.46 (m, 3H), 7.04-7.12 (m, 3H), 6.78 (d,1H), 6.73 (dd, 1H), 6.60 (s, 1H), 6.55 (d, 1H), 3.40 (t, 2H), 3.29-3.36(m, 2H), 3.27 (s, 3H), 3.01-3.08 (m, 4H), 2.76 (s, 2H), 2.25 (t, 2H),2.06-2.15 (m, 4H), 1.97 (s, 2H), 1.78-1.86 (m, 2H), 1.38 (t, 2H), 0.93(s, 6H).

Example 3184-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-methoxypropyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 1E andEXAMPLE 317A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz, pyridine-ds)δ 12.39 (s, 1H), 9.21 (d, 1H), 8.86 (t, 1H), 8.15-8.24 (m, 2H),7.42-7.50 (m, 3H), 7.38 (d, 1H), 7.04-7.13 (m, 3H), 6.73-6.81 (m, 4H),6.67 (d, 1H), 3.39 (t, 2H), 3.32 (q, 2H), 3.27 (s, 3H), 2.96-3.07 (m,4H), 2.76 (s, 2H), 2.25 (t, 2H), 2.07-2.16 (m, 4H), 1.97 (s, 2H),1.77-1.87 (m, 2H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 3194-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamideExample 319A 4-(2-cyanoethylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting 3-aminopropanenitrile for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 319B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 319A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz, pyridine-ds)δ 9.26 (d, 1H), 9.06 (t, 1H), 8.34 (dd, 1H), 8.18 (d, 1H), 7.51-7.57 (m,2H), 7.39-7.47 (m, 3H), 7.04-7.11 (m, 3H), 7.00 (d, 1H), 6.74 (dd, 1H),6.60 (s, 1H), 6.54 (d, 1H), 3.83 (q, J=6.7 Hz, 2H), 3.01-3.08 (m, 4H),2.98 (t, 2H), 2.76 (s, 2H), 2.25 (t, 2H), 2.07-2.15 (m, 4H), 1.97 (s,2H), 1.38 (t, 2H), 0.93 (s, 6H).

Example 3204-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 1E andEXAMPLE 319A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz, pyridine-ds)δ 12.41 (s, 1H), 9.16 (d, 1H), 9.05 (t, 1H), 8.31 (dd, 1H), 8.17 (d,1H), 7.39 (d, 1H), 7.05-7.13 (m, 3H), 6.99 (d, 1H), 6.78 (dd, 1H),6.72-6.76 (m, 2H), 6.66 (d, 1H), 3.83 (q, 2H), 3.01-3.07 (m, 4H), 2.98(t, 2H), 2.76 (s, 2H), 2.25 (t, 2H), 2.08-2.16 (m, 4H), 1.97 (s, 2H),1.39 (t, 2H), 0.94 (s, 6H).

Example 3214-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(3R)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 310C byreplacing EXAMPLE 310A with 5-aminomethyl-admantan-2-ol. ¹H NMR (500MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 2H), 8.57 (d, 1H), 8.51 (t, 1H),7.76 (dd, 1H), 7.50 (d, 1H), 7.38-7.42 (m, 2H), 7.33 (d, 2H), 7.11-7.16(m, 2H), 7.03 (d, 2H), 6.86 (dd, 1H), 6.65 (dd, 1H), 6.39 (s, 1H), 6.14(d, 1H), 4.61 (d, 1H), 3.63 (d, 1H), 3.13 (d, 2H), 3.03 (s, 4H), 2.73(s, 2H), 2.11-2.21 (m, 6H), 2.04 (d, 2H), 1.95 (s, 2H), 1.78-1.86 (m,3H), 1.49-1.60 (m, 6H), 1.38 (t, 2H), 1.29 (d, 2H), 0.92 (s, 6H).

Example 3224-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[Cis-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 310C byreplacing EXAMPLE 310A with 5-aminomethyl-admantan-2-ol. ¹H NMR (500MHz, dimethylsulfoxide-d₆) δ 11.16 (s, 2H), 8.57 (d, 1H), 8.52 (t, 1H),7.71-7.80 (m, 1H), 7.51 (d, 1H), 7.37-7.42 (m, 2H), 7.33 (d, 2H),7.09-7.17 (m, 2H), 7.03 (d, 2H), 6.85 (dd, 1H), 6.65 (dd, 1H), 6.39 (s,1H), 6.14 (d, 1H), 4.61 (d, 1H), 3.61 (d, 1H), 3.08 (d, 2H), 3.03 (s,4H), 2.72 (s, 2H), 2.09-2.21 (m, 6H), 1.82-1.96 (m, 7H), 1.55-1.69 (m,4H), 1.49 (s, 2H), 1.38 (t, 2H), 1.19-1.27 (m, 3H), 0.92 (s, 6H).

Example 3234-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phenyl}sulfonyl)benzamideExample 323A 3-nitro-4-(3,3,3-trifluoropropylamino)benzenesulfonamide

This example was prepared by substituting 3,3,3-trifluoropropan-1-aminefor (tetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 1F.

Example 323B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 323A for EXAMPLE 1Fand EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.34 (s, 1H), 11.19 (s, 1H), 8.53 (m, 1H), 8.47(s, 1H), 7.74 (dd, 1H), 7.54 (d, 1H), 7.34 (d, 2H), 7.25 (m, 1H), 7.13(d, 1H), 6.99 (m, 4H), 6.67 (d, 1H), 6.36 (d, 1H), 6.24 (m, 2H), 3.65(q, 2H), 3.01 (m, 4H), 2.68 (m, 4H), 2.16 (m, 6H), 1.95 (s, 2H), 1.38(t, 2H), 0.93 (s, 6H).

Example 3244-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 323A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.06 (s, 1H),8.44 (m, 2H), 7.75 (dd, 1H), 7.54 (d, 1H), 7.33 (m, 4H), 7.02 (m, 3H),6.90 (d, 1H), 6.76 (dd, 1H), 6.58 (dd, 1H), 6.33 (m, 1H), 6.15 (d, 1H),3.63 (q, 2H), 2.97 (m, 4H), 2.68 (m, 4H), 2.16 (m, 6H), 1.95 (s, 2H),1.38 (t, 2H), 0.92 (s, 6H).

Example 325N-({5-bromo-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamideExample 325A5-bromo-6-((tetrahydro-2H-pyran-4-yl)methylamino)pyridine-3-sulfonamide

The mixture of EXAMPLE 329A (93 mg),(tetrahydro-2H-pyran-4-yl)methanamine (40 mg) and triethylamine (0.144mL) in anhydrous dioxane (4 mL) was heated at 110° C. overnight. Theorganic solvent was removed under vacuum. The residue was suspended indichloromethane. The solid was filtered and dried to afford the titlecompound.

Example 325BN-({5-bromo-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 26Cand EXAMPLE 325A for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.28 (s, 1H), 11.10 (s, 1H), 8.38 (d, 1H), 7.93(d, 1H), 7.57 (d, 1H), 7.32 (m, 4H), 7.22 (d, 1H), 7.02 (m, 3H), 6.71(dd, 1H), 6.51 (d, 1H), 6.27 (m, 2H), 3.82 (dd, 2H), 3.31 (m, 2H), 3.23(m, 2H), 3.05 (m, 4H), 2.74 (s, 2H), 2.16 (m, 6H), 1.95 (s, 2H), 1.88(m, 1H), 1.55 (m, 2H), 1.37 (m, 2H), 1.18 (m, 2H), 0.92 (s, 6H).

Example 3264-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1,1-dioxidotetrahydrothien-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 337A for4-chloro-3-nitrobenzene sulfonamide and(1,1-dioxidotetrahydrothien-3-yl)methylamine hydrochloride for1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A. ¹H NMR (400MHz, dimethylsulfoxide-d₆) δ 11.25 (s, 1H), 8.71 (m, 1H), 8.51 (d, 1H),7.72 (dd, 1H), 7.53 (d, 1H), 7.34 (d, 2H), 7.29 (m, 1H), 7.18 (d, 1H),7.12 (d, 1H), 7.04 (d, 2H), 6.98 (m, 1H), 6.70 (dd, 1H), 6.44 (d, 1H),6.26 (dd, 2H), 3.55 (t, 2H), 3.27 (m, 2H), 3.04 (m, 5H), 2.91 (m, 1H),2.74 (s, 3H), 2.28 (m, 1H), 2.16 (m, 6H), 1.95 (s, 2H), 1.85 (m, 1H),1.38 (t, 2H), 0.92 (s, 6H).

Example 3274-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 306D for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.16 (s, 2H),8.41 (d, 1H), 8.10 (dd, 1H), 7.51 (d, 1H), 7.39-7.46 (m, 3H), 7.34 (d,2H), 7.16 (s, 1H), 7.04 (d, 2H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.40 (d,1H), 6.15 (d, 1H), 4.38 (d, 2H), 3.76-3.80 (m, 2H), 3.56-3.61 (m, 2H),3.05 (s, 4H), 2.78 (s, 2H), 2.12-2.23 (m, 6H), 1.95 (s, 2H), 1.80-1.89(m, 4H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 3284-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-(methylamino)-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamideExample 328A4-(methylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

This example was prepared by substituting EXAMPLE 159C for4-fluoro-3-nitrobenzenesulfonamide and methylamine for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 328B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-(methylamino)-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 328A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 1H),8.17 (d, 1H), 7.91 (dd, 1H), 7.49 (d, 1H), 7.40 (m, 3H), 7.33 (d, 2H),7.16 (m, 1H), 7.04 (d, 2H), 6.87 (m, 2H), 6.65 (dd, 1H), 6.40 (m, 1H),6.14 (d, 1H), 3.03 (m, 4H), 2.91 (d, 3H), 2.73 (s, 2H), 2.15 (m, 6H),1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 329N-{[5-bromo-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamideExample 329A 5-bromo-6-chloropyridine-3-sulfonamide

5-Bromo-6-chloropyridine-3-sulfonyl chloride (8.2 g) in methanol (20 mL)was cooled to 0° C. To this mixture was added 7N NH₃ in methanol (80mL). The reaction mixture was stirred overnight. The solvent was removedat low temperature, and the residue was partitioned between ethylacetate and water. The aqueous layer was extracted with ethyl acetatethree times. The combined organic layers were washed with brine, dried(MgSO₄), filtered, and concentrated. The solid was purified by flashcolumn chromatography on silica gel using 10-50% ethyl acetate inhexanes to give the title compound.

Example 329B5-bromo-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

(Tetrahydro-2H-pyran-4-yl)methanol (0.65 g) in tetrahydrofuran (20 mL)was treated with 60% sodium hydride (0.895 g). The reaction mixture wasstirred for 10 minutes. To this mixture was added EXAMPLE 329A (1.519g). The reaction mixture was stirred overnight. It was poured intowater, neutralized with 10% aqueous HCl, and extracted with ethylacetate three times. The combined organic layers were washed with brine,dried over MgSO₄, filtered, and concentrated. The residue was purifiedwith flash column chromatography on silica gel eluting with 20%-60%ethyl acetate in hexanes to give the title compound.

Example 329CN-{[5-bromo-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 329B for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.15 (s, 1H),8.60 s, 1H), 8.38 (d, 1H), 7.54 (d, 1H), 7.38-7.42 (m, 2H), 7.34 (d,2H), 7.17 (s, 1H), 7.04 (d, 2H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.39 (s,1H), 6.14 (d, 1H), 4.25 (d, 2H), 3.87 (dd, 2H), 3.05 (s, 4H), 2.80 (s,2H), 2.25 (s, 4H), 2.12-2.14 (m, 4H), 1.95 (s, 2H), 1.63-1.66 (m, 2H),1.37-1.40 (m, 2H), 0.92 (s, 6H).

Example 3304-(4-{[4-(4-chlorophenyl)-6-isopropoxypyridin-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 330A1-((4-(4-chlorophenyl)-6-isopropoxypyridin-3-yl)methyl)piperazine

This example was prepared by substituting EXAMPLE 307F for EXAMPLE 1A inEXAMPLE 1B.

Example 330B ethyl2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-6-isopropoxypyridin-3-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 330A for EXAMPLE 20Cand EXAMPLE 26A for EXAMPLE 20A in EXAMPLE 20D.

Example 330C2-(1H-indol-5-yloxy)-4-(4-((4-(4-chlorophenyl)-6-isopropoxypyridin-3-yl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 330B for EXAMPLE 1D inEXAMPLE 1E.

Example 330D4-(4-{[4-(4-chlorophenyl)-6-isopropoxypyridin-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 330C for EXAMPLE 26Cin EXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.21, (s, 1H),11.17 (s, 1H), 8.63 (t, 1H), 8.59 (d, 1H), 8.08 (s, 1H), 7.79 (dd, 1H),7.54-7.56 (m, 3H), 7.47 (d, 2H), 7.38-7.42 (m, 2H), 7.15 (d, 1H), 7.10(d, 1H), 6.87 (dd, 1H), 6.68 (dd, 1H), 6.59 (s, 1H), 6.39 (s, 1H), 6.17(d, 1H), 5.23-5.28 (m, 1H), 3.85 (dd, 2H), 3.24-3.31 (m, 4H), 3.02 (s,4H), 2.29 (s, 4H), 1.86-1.91 (m, 1H), 1.61-1.63 (m, 2H), 1.28 (d, 6H).

Example 3314-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[6-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(1,3-thiazol-2-yl)pyridin-3-yl]sulfonyl}benzamideExample 331A6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-(thiazol-2-yl)pyridine-3-sulfonamide

A mixture of EXAMPLE 329B (0.070 g), 2-(tributylstannyl)thiazole (0.090g), and tetrakis(triphenylphosphine)palladium(0) (0.069 g) in dioxane (2mL) was heated at 90° C. for 4 hours. After cooling, the mixture wasloaded onto a silica gel column and eluting with 1:3 ethylacetate:hexanes to give the title compound.

Example 331B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[6-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(1,3-thiazol-2-yl)pyridin-3-yl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 331A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.14 (s, 1H),9.09 (s, 1H), 8.73 (s, 1H), 8.06 (d, 1H), 7.98 (d, 1H), 7.50 (d, 1H),7.37-7.38 (m, 2H), 7.33 (d, 2H), 7.17 (d, 1H), 7.03 (d, 2H), 6.84 (dd,1H), 6.62 (dd, 1H), 6.37 (s, 1H), 6.11 (d, 1H), 4.46 (d, 2H), 3.91 (dd,2H), 3.36-3.39 (m, 4H), 3.02 (s, 4H), 2.76 (s, 2H), 2.12-2.20 (s, 8H),1.94 (s, 2H), 1.45-1.47 (m, 2H), 1.37 (t, 2H), 0.91 (s, 6H).

Example 3324-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(2-methoxyethyl)amino]carbonyl}phenyl)sulfonyl]benzamideExample 332A N-(2-methoxyethyl)-4-sulfamoylbenzamide

This example was prepared by substituting 2-methoxyethanamine for(tetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 308A.

Example 332B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(2-methoxyethyl)amino]carbonyl}phenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 332A for EXAMPLE 1Fand EXAMPLE 26C for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.28 (br s, 1H), 11.17 (s, 1H), 8.71 (m, 1H),7.94 (m, 4H), 7.48 (d, 1H), 7.41 (m, 2H), 7.33 (d, 2H), 7.21 (d, 1H),7.03 (d, 2H), 6.88 (dd, 1H), 6.63 (dd, 1H), 6.42 (t, 1H), 6.13 (d, 1H),3.45 (m, 4H), 3.27 (s, 3H), 3.03 (m, 4H), 2.73 (br s, 2H), 2.16 (m, 6H),1.95 (br s, 2H), 1.38 (m, 2H), 0.92 (s, 6H).

Example 3334-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-5-yloxy)benzamideExample 333A5-cyano-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

A mixture of EXAMPLE 329B (0.702 g), dicyanozinc (0.129 g), andtetrakis(triphenylphosphine)palladium(0) (0.231 g) inN,N-dimethylformamide (2 mL) was degassed via vacuum/nitrogen cyclethree times. The reaction mixture was heated at 120° C. for 3 hours.After cooling, it was poured into water and extracted with ethyl acetatethree times. The combined organic layers were washed with brine, driedover MgSO₄, filtered, and concentrated. The residue was purified withflash column chromatography on silica gel eluting with 20%-60% ethylacetate in hexanes to give the title compound.

Example 333B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 333A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 1H),8.84 (d, 1H), 8.64 (d, 1H), 7.57 (d, 1H), 7.38-7.41 (m, 4H), 7.12 (d,1H), 7.08 (d, 2H), 6.87 (dd, 1H), 6.71 (dd, 1H), 6.38 (s, 1H), 6.23 (d,1H), 4.31 (d, 2H), 3.88 (dd, 2H), 3.54 (br s, 2H), 3.02 (br s, 4H), 2.76(br s, 2H), 2.18 (s, 4H), 2.01 (s, 2H), 1.63-1.66 (m, 2H), 1.49 (t, 2H),0.94 (s, 6H).

Example 334N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting 1-acetylpiperidin-4-amine for1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 310B for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.16 (br s, 1H), 8.58 (d, 1H), 8.25 (d, 1H),7.81 (dd, 1H), 7.51 (d, 1H), 7.43-7.37 (m, 2H), 7.34 (d, 2H), 7.19 (d,1H), 7.15 (d, 1H), 7.04 (d, 2H), 6.85 (dd, 1H), 6.65 (dd, 1H), 6.39 (t,1H), 6.15 (d, 1H), 4.32-4.23 (m, 1H), 3.96-3.77 (m, 2H), 3.21 (m, 2H),3.03 (m, 4H), 2.80 (m, 2H), 2.73 (br s, 2H), 2.16 (m, 6H), 2.02 (s, 3H),1.95 (br s, 2H), 1.65-1.44 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 3354-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting1-(methylsulfonyl)piperidin-4-amine for1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.15 (br s, 1H), 8.59 (d, 1H), 8.25 (d, 1H),7.82 (dd, 1H), 7.51 (d, 1H), 7.43-7.38 (m, 2H), 7.34 (d, 2H), 7.14 (m,2H), 7.04 (d, 2H), 6.85 (dd, 1H), 6.65 (dd, 1H), 6.39 (t, 1H), 6.15 (d,1H), 3.80 (m, 1H), 3.57 (m, 2H), 3.04 (m, 4H), 2.95 (m, 2H), 2.92 (br s,3H), 2.73 (m, 2H), 2.15 (m, 6H), 2.06-1.98 (m, 2H), 1.95 (br s, 2H),1.70 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 3364-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamideExample 336A 4-((1,4-dioxan-2-yl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared as described in EXAMPLE 1F by replacing(tetrahydro-2H-pyran-4-yl)methanamine with (1,4-dioxan-2-yl)methanamine.

Example 336B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 175F byreplacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 26C and EXAMPLE 336A,respectively. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.16 (s, 2H),8.54-8.63 (m, 2H), 7.82 (dd, 1H), 7.50 (d, 1H), 7.38-7.42 (m, 2H), 7.33(d, 2H), 7.16 (d, 1H), 7.10 (d, 1H), 7.03 (d, 2H), 6.86 (dd, 1H), 6.65(dd, 1H), 6.39 (s, 1H), 6.14 (d, 1H), 3.76-3.82 (m, 3H), 3.57-3.68 (m,2H), 3.45-3.52 (m, 2H), 3.36-3.42 (m, 1H), 3.03 (s, 4H), 2.73 (d, 2H),2.10-2.22 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 337N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamideExample 337A

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 1E and4-chloro-3-nitrobenzenesulfonamide for EXAMPLE 1F in EXAMPLE 1G.

Example 337BN-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting 1-acetylpiperidin-4-amine for1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 337A for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.24 (br s, 1H), 8.50 (d, 1H), 8.24 (d, 1H),7.73 (dd, 1H), 7.52 (d, 1H), 7.34 (d, 2H), 7.27 (t, 1H), 7.19-7.13 (m,2H), 7.04 (t, 2H), 6.97 (t, 1H), 6.70 (dd, 1H), 6.42 (d, 1H), 6.27 (dd,1H), 6.24 (t, 1H), 4.29 (m, 1H), 3.97-3.78 (m, 2H), 3.22 (m, 2H), 3.05(m, 4H), 2.81 (m, 2H), 2.72 (br s, 2H), 2.15 (m, 6H), 2.03 (s, 3H), 1.95(br s, 2H), 1.66-1.44 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 3384-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting1-(methylsulfonyl)piperidin-4-amine for1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 337A for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.24 (br s, 1H), 8.50 (d, 1H), 8.25 (d, 1H),7.74 (dd, 1H), 7.52 (d, 1H), 7.34 (d, 2H), 7.27 (t, 1H), 7.17 (d, 1H),7.12 (d, 1H), 7.04 (d, 2H), 6.97 (t, 1H), 6.70 (dd, 1H), 6.42 (d, 1H),6.27 (d, 1H), 6.24 (t, 1H), 3.81 (m, 1H), 3.58 (m, 2H), 3.05 (m, 4H),2.96 (m, 2H), 2.92 (s, 3H), 2.74 (m, 2H), 2.16 (m, 6H), 2.06-1.98 (m,2H), 1.95 (br s, 2H), 1.70 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 3394-(4-{[4′-chloro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 339A methyl2-(1H-indol-5-yloxy)-4-(4-(2-bromo-4-(trifluoromethyl)benzyl)piperazin-1-yl)benzoate

This example was prepared by substituting4-trifluoromethyl-2-bromobenzaldehyde for EXAMPLE 27C and EXAMPLE 150Afor tert-butyl piperazine-1-carboxylate in EXAMPLE 1A.

Example 339B methyl2-(1H-indol-5-yloxy)-4-(4-((4′-chloro-5-(trifluoromethyl)biphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 339A for2-fluoro-4-iodo-5-methylpyridine in EXAMPLE 307A.

Example 339C2-(1H-indol-5-yloxy)-4-(4-((4′-chloro-5-(trifluoromethyl)biphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 339B for EXAMPLE 1D inEXAMPLE 1E.

Example 339D4-(4-{[4′-chloro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 339C for EXAMPLE 26Cin EXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.24, (s, 1H),11.17 (s, 1H), 8.63 (t, 1H), 7.79 (dd, 1H), 7.72 (m, 2H), 7.38-7.53 (m,8H), 7.15 (d, 1H), 7.10 (d, 1H), 6.87 (dd, 1H), 6.67 (dd, 1H), 6.39 (s,1H), 6.16 (d, 1H), 3.85 (dd, 2H), 3.41 (s, 2H), 3.24-3.31 (m, 6H), 3.04(s, 4H), 2.29 (s, 4H), 1.60-1.63 (m, 2H), 1.24-1.28 (m, 2H).

Example 3404-(4-{[4′-chloro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 339C for EXAMPLE 26Cand EXAMPLE 279A for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.40, (s, 1H), 11.17 (s, 1H), 8.41 (d, 1H),8.07 (dd, 1H), 7.70-7.74 (m, 2H), 7.38-7.53 (m, 8H), 7.16 (d, 1H), 6.87(dd, 1H), 6.67 (dd, 1H), 6.40 (s, 1H), 6.17 (d, 1H), 4.09 (d, 2H), 3.88(dd, 2H), 3.42 (s, 2H), 3.05 (s, 4H), 2.30 (s, 4H), 2.00-2.05 (m, 1H),1.63-1.66 (m, 2H), 1.31-1.37 (m, 2H).

Example 3414-{4-[(5-tert-butyl-4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 341A methyl2-(1H-indol-5-yloxy)-4-(4-(2-bromo-4-tert-butylbenzyl)piperazin-1-yl)benzoate

This example was prepared by substituting4-tert-butyl-2-bromobenzaldehyde for EXAMPLE 27C and EXAMPLE 150A fortert-butyl piperazine-1-carboxylate in EXAMPLE 1A.

Example 341B methyl2-(1H-indol-5-yloxy)-4-(4-((5-tert-butyl-4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 341A for2-fluoro-4-iodo-5-methylpyridine in EXAMPLE 307A.

Example 341C2-(1H-indol-5-yloxy)-4-(4-((5-tert-butyl-4′-chlorobiphenyl-2-yl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 341B for EXAMPLE 1D inEXAMPLE 1E.

Example 341D4-{4-[(5-tert-butyl-4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 341C for EXAMPLE 26Cin EXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.22, (s, 1H),11.16 (s, 1H), 8.62 (t, 1H), 8.58 (d, 1H), 7.79 (dd, 1H), 7.53 (d, 1H),7.34-7.44 (m, 8H), 7.18 (s, 1H), 7.14 (d, 1H), 7.09 (d, 1H), 6.86 (dd,1H), 6.67 (dd, 1H), 6.39 (s, 1H), 6.17 (d, 1H), 3.85 (dd, 2H), 3.24-3.30(m, 6H), 3.04 (s, 4H), 2.29 (s, 4H), 1.86-1.91 (m, 1H), 1.60-1.63 (m,2H), 1.28 (s, 9H).

Example 3424-{4-[(5-tert-butyl-4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 341C for EXAMPLE 26Cand EXAMPLE 279A for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.25, (br s, 1H), 11.16 (s, 1H), 8.40 (d, 1H),8.06 (dd, 1H), 7.52 (d, 1H), 7.35-7.46 (m, 8H), 7.19 (s, 1H), 7.15 (d,1H), 6.85 (dd, 1H), 6.66 (dd, 1H), 6.39 (s, 1H), 6.17 (d, 1H), 4.08 (d,2H), 3.88 (dd, 2H), 3.05 (s, 4H), 2.32 (s, 4H), 1.64 (dd, 2H), 1.32-1.37(m, 2H), 1.28 (s, 9H).

Example 3434-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}sulfonyl)benzamideExample 343A 3-nitro-4-(2,2,2-trifluoroethylamino)benzenesulfonamide

This example was prepared by substituting 2,2,2-trifluoroethanamine for(tetrahydro-2H-pyran-4-yl)methanamine in EXAMPLE 1F.

Example 343B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 343A for EXAMPLE 1Fand EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 10.98 (s, 1H), 8.41 (m, 2H), 7.75 (dd, 1H), 7.54(d, 1H), 7.34 (d, 2H), 7.28 (m, 2H), 7.06 (m, 3H), 6.93 (m, 1H), 6.70(dd, 1H), 6.53 (dd, 1H), 6.30 (m, 1H), 6.14 (d, 1H), 4.32 (m, 2H), 2.93(m, 4H), 2.71 (s, 2H), 2.16 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92(s, 6H).

Example 3444-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 343A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.05 (s, 1H),8.40 (m, 2H), 7.77 (dd, 1H), 7.60 (d, 1H), 7.34 (d, 2H), 7.18 (m, 1H),7.12 (d, 1H), 7.04 (m, 3H), 6.88 (t, 1H), 6.58 (dd, 1H), 6.22 (m, 3H),4.33 (m, 2H), 2.93 (m, 4H), 2.71 (s, 2H), 2.16 (m, 6H), 1.95 (s, 2H),1.38 (t, 2H), 0.93 (s, 6H).

Example 3454-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}phenyl)sulfonyl]benzamideExample 345A 3-sulfamoyl-N-((tetrahydro-2H-pyran-4-yl)methyl)benzamide

This example was prepared by substituting 3-sulfamoylbenzoic acid for4-sulfamoylbenzoic acid in EXAMPLE 308A.

Example 345B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}phenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 345A for EXAMPLE 1Fand EXAMPLE 26C for EXAMPLE 1E in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.28 (br s, 1H), 11.18 (s, 1H), 8.75 (t, 1H),8.41 (m, 1H), 8.10 (d, 1H), 8.01 (d, 1H), 7.60 (t, 1H), 7.48 (d, 1H),7.41 (m, 2H), 7.33 (d, 2H), 7.23 (d, 1H), 7.03 (d, 2H), 6.88 (dd, 1H),6.83 (dd, 1H), 6.42 (t, 1H), 6.11 (d, 1H), 3.83 (dd, 2H), 3.19 (m, 4H),3.02 (m, 4H), 2.73 (m, 2H), 2.16 (m, 6H), 1.94 (br s, 2H), 1.80 (m, 1H),1.58 (dd, 2H), 1.37 (t, 2H), 1.24 (m, 2H), 0.92 (s, 6H).

Example 3464-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamideExample 346A (R)-4-((1,4-dioxan-2-yl)methoxy)-3-nitrobenzenesulfonamide

The racemic mixture of EXAMPLE 297A was resolved on a SFC chiral ADcolumn to provide the title compound.

Example 346B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 175F byreplacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 26C and EXAMPLE 346A,respectively. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.16 (s, 2H),8.39 (d, 1H), 8.06 (dd, 1H), 7.51 (d, 1H), 7.38-7.43 (m, 3H), 7.34 (d,2H), 7.15 (d, 1H), 7.04 (d, 2H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.39 (s,1H), 6.15 (d, 1H), 4.20-4.28 (m, 2H), 3.85-3.91 (m, 1H), 3.82 (dd, 1H),3.74-3.78 (m, 1H), 3.59-3.69 (m, 2H), 3.40-3.51 (m, 2H), 3.05 (s, 4H),2.78 (s, 2H), 2.23 (s, 4H), 2.14 (s, 2H), 1.95 (s, 2H), 1.38 (t, 2H),0.92 (s, 6H).

Example 3474-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2S)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamideExample 347A (S)-4-((1,4-dioxan-2-yl)methoxy)-3-nitrobenzenesulfonamide

The racemic mixture of EXAMPLE 297A was resolved on a SFC chiral ADcolumn to provide the title compound.

Example 347B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2S)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 175F byreplacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 26C and EXAMPLE 347A,respectively. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.16 (s, 2H),8.39 (d, 1H), 8.06 (dd, 1H), 7.51 (d, 1H), 7.38-7.43 (m, 3H), 7.34 (d,2H), 7.15 (d, 1H), 7.04 (d, 2H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.39 (s,1H), 6.15 (d, 1H), 4.20-4.28 (m, 2H), 3.85-3.91 (m, 1H), 3.82 (dd, 1H),3.74-3.78 (m, 1H), 3.59-3.69 (m, 2H), 3.40-3.51 (m, 2H), 3.05 (s, 4H),2.78 (s, 2H), 2.23 (s, 4H), 2.14 (s, 2H), 1.95 (s, 2H), 1.38 (t, 2H),0.92 (s, 6H).

Example 3484-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamideExample 348A4-(3-morpholinopropylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

This example was prepared by substituting EXAMPLE 159C for4-fluoro-3-nitrobenzenesulfonamide and 3-morpholinopropan-1-amine for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 348B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide5-yloxy)-N-({4-(methylamino)-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 348A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 1H),8.17 (d, 1H), 7.91 (dd, 1H), 7.49 (d, 1H), 7.40 (m, 3H), 7.33 (d, 2H),7.15 (d, 1H), 7.03 (m, 3H), 6.85 (dd, 1H), 6.64 (dd, 1H), 6.40 (s, 1H),6.13 (d, 1H), 3.59 (m, 4H), 3.38 (m, 4H), 3.02 (m, 4H), 2.72 (s, 2H),2.40 (m, 6H), 2.15 (m, 6H), 1.95 (s, 2H), 1.73 (m, 2H), 0.92 (s, 6H).

Example 3494-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 26Cand EXAMPLE 348A for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.25 (s, 1H), 11.08 (m, 1H), 8.12 (d, 1H), 7.81(dd, 1H), 7.52 (d, 1H), 7.36 (m, 3H), 7.28 (m, 1H), 7.19 (d, 1H), 7.04(d, 2H), 6.98 (m, 2H), 6.69 (dd, 1H), 6.44 (d, 1H), 6.25 (m, 2H), 3.60(m, 4H), 3.38 (m, 2H), 3.03 (m, 4H), 2.73 (s, 2H), 2.43 (m, 6H), 2.16(m, 6H), 1.95 (s, 2H), 1.73 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 350N-({5-bromo-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 325A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.19 (s, 1H),11.02 (s, 1H), 8.47 (d, 1H), 8.07 (d, 1H), 7.55 (d, 1H), 7.39 (m, 5H),7.25 (d, 1H), 7.03 (d, 2H), 6.89 (dd, 1H), 6.65 (dd, 1H), 6.42 (s, 1H),6.11 (d, 1H), 3.82 (dd, 2H), 3.31 (m, 2H), 3.24 (m, 2H), 3.03 (m, 4H),2.72 (s, 2H), 2.15 (m, 6H), 1.94 (s, 2H), 1.89 (m, 1H), 1.54 (m, 2H),1.38 (t, 2H), 1.17 (m, 2H), 0.92 (s, 6H).

Example 3514-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamideExample 351A4-(2-morpholinoethylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide

This example was prepared by substituting EXAMPLE 159C for4-fluoro-3-nitrobenzenesulfonamide and 2-morpholinoethanamine for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 351B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 351A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.22 (s, 1H),11.17 (s, 1H), 8.17 (d, 1H), 7.92 (dd, 1H), 7.61 (s, 1H), 7.48 (d, 1H),7.40 (m, 2H), 7.33 (d, 2H), 7.15 (d, 1H), 7.03 (d, 2H), 6.93 (d, 1H),6.85 (dd, 1H), 6.64 (dd, 1H), 6.40 (s, 1H), 6.13 (m, 1H), 3.57 (m, 4H),3.35 (m, 2H), 3.02 (m, 4H), 2.72 (s, 2H), 2.58 (t, 2H), 2.42 (m, 4H),2.15 (m, 6H), 1.95 (s, 2H), 1.37 (m, 2H), 0.92 (s, 6H).

Example 3524-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-indol-5-yloxy)benzamideExample 352A5-cyano-6-((tetrahydro-2H-pyran-4-yl)methylamino)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 325A for EXAMPLE 329Bin EXAMPLE 333A.

Example 352B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 352A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.18 (s, 1H),8.65 (d, 1H), 8.27 (d, 1H), 8.15 (s, 1H), 7.56 (d, 1H), 7.41 (m, 2H),7.34 (d, 2H), 7.22 (d, 1H), 7.04 (d, 2H), 6.88 (dd, 1H), 6.65 (dd, 1H),6.41 (m, 1H), 6.12 (d, 1H), 3.82 (dd, 2H), 3.33 (m, 2H), 3.24 (t, 2H),3.04 (m, 4H), 2.75 (s, 2H), 2.16 (m, 6H), 1.95 (s, 2H), 1.89 (m, 1H),1.55 (m, 2H), 1.38 (t, 2H), 1.19 (m, 2H), 0.91 (s, 6H).

Example 3534-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)oxy]-3-nitrophenyl}sulfonyl)benzamideExample 353A 4-(1-methylpiperidin-4-yloxy)-3-nitrobenzenesulfonamide

To a mixture of 1-methylpiperidin-4-ol (0.542 g) in tetrahydrofuran (10mL) at 0° C. was added NaH (60% in mineral oil) (0.753 g). Afterstirring for 15 minutes, 4-fluoro-3-nitrobenzenesulfonamide (1.036 g)was added as a solution in tetrahydrofuran (10 mL). The reaction wasremoved from the ice bath and allowed to warm to room temperature. After1 hour, the reaction was poured into water and the pH adjusted to −7with 1N aqueous HCl. The reaction was extracted with dichloromethane(3×100 mL), washed with brine, dried over magnesium sulfate, filtered,and concentrated. The product was suspended in dichloromethane (mL),sonicated and then filtered to give the title compound.

Example 353B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)oxy]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 353A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide) δ 11.03 (s, 1H), 8.21 (d, 1H), 7.87 (dd, 1H), 7.55(d, 1H), 7.33 (dd, 4H), 7.25 (d, 1H), 7.04 (d, 2H), 6.98 (d, 1H), 6.73(dd, 1H), 6.56 (d, 1H), 6.33 (s, 1H), 6.14 (d, 1H), 4.79 (s, 1H), 2.96(s, 6H), 2.72 (s, 2H), 2.57 (s, 3H), 2.18 (s, 6H), 1.94 (m, 6H), 1.39(m, 2H), 0.92 (s, 6H).

Example 3544-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamideExample 354A4-((1-methylpiperidin-4-yl)methoxy)-3-nitrobenzenesulfonamide

This example was prepared by substituting(1-methylpiperidin-4-yl)methanol for 1-methylpiperidin-4-ol in EXAMPLE353A.

Example 354B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 354A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide) δ 11.01 (s, 1H), 8.19 (d, 1H), 7.87 (dd, 1H), 7.55(d, 1H), 7.39-7.26 (m, 4H), 7.16 (d, 1H), 7.08-7.01 (m, 2H), 6.96 (d,1H), 6.72 (dd, 1H), 6.54 (d, 1H), 6.32 (s, 1H), 6.14 (d, 1H), 4.05 (d,2H), 2.95 (s, 4H), 2.89-2.59 (m, 7H), 2.17 (s, 6H), 2.00-1.78 (m, 5H),1.53 (s, 2H), 1.37 (m, 2H), 0.92 (s, 6H).

Example 3554-(4-{[4-(4-chlorophenyl)-1-(3-hydroxypropyl)-1,2,5,6-tetrahydropyridin-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 355A tert-butyl4-chloro-3-formyl-5,6-dihydropyridine-1(2H)-carboxylate

To N,N-dimethylformamide (3.87 mL) at 0° C., phosphorus oxychloride(3.73 mL) was added dropwise, maintaining the temperature below 5° C.The resulting mixture was diluted with dichloromethane (15 mL) andstirred at room temperature for 1.5 hours. The reaction was then cooledin an ice bath. tert-Butyl 4-oxopiperidine-1-carboxylate (4.98 g) wasadded as a solution in dichloromethane (20 mL) and the reaction wasstirred at room temperature for 1 hour. The reaction mixture was pouredover ice and solid sodium acetate, stirred for 15 minutes, and extractedwith dichloromethane. The extracts were washed thoroughly with water andwith brine, dried over MgSO₄, filtered, and concentrated to obtain thetitle compound.

Example 355B tert-butyl4-(4-chlorophenyl)-3-formyl-5,6-dihydropyridine-1(2H)-carboxylate

EXAMPLE 355A (6.14 g), 4-chlorophenylboronic acid (4.10 g) andpalladium(II) acetate (0.112 g) were combined in water to give asuspension. Potassium carbonate (8.98 g) and tetrabutylammonium bromide(4.03 g) were added. The resulting mixture was stirred at 45° C.overnight, cooled, and the reaction mixture was diluted with ethylacetate (200 mL) in order to dissolve any insoluble material, thenwashed thoroughly with water, dried over MgSO₄, filtered, andconcentrated. The crude material was purified by flash chromatographyeluting with a gradient of 10% ethyl acetate/hexanes to 40% ethylacetate/hexanes.

Example 355C tert-butyl3-((4-(3-(1H-indol-4-yloxy)-4-(methoxycarbonyl)phenyl)piperazin-1-yl)methyl)-4-(4-chlorophenyl)-5,6-dihydropyridine-1(2H)-carboxylate

This example was prepared by substituting EXAMPLE 355B for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 68B for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 355D methyl2-(1H-indol-4-yloxy)-4-(4-((4-(4-chlorophenyl)-1,2,5,6-tetrahydropyridin-3-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 355C for EXAMPLE 1A inEXAMPLE 1B.

Example 355E methyl2-(1H-indol-4-yloxy)-4-(4-((4-(4-chlorophenyl)-1-(3-hydroxypropyl)-1,2,5,6-tetrahydropyridin-3-yl)methyl)piperazin-1-yl)benzoate

EXAMPLE 355D (539 mg), 3-bromopropan-1-ol (83 mg) and triethylamine(0.42 mL) were combined in acetonitrile. The mixture was heated to 60°C. overnight, concentrated and then triturated with ether and filteredto give the title compound.

Example 355F2-(1H-indol-4-yloxy)-4-(4-((4-(4-chlorophenyl)-1-(3-hydroxypropyl)-1,2,5,6-tetrahydropyridin-3-yl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 355E for EXAMPLE 1D inEXAMPLE 1E.

Example 355G4-(4-{[4-(4-chlorophenyl)-1-(3-hydroxypropyl)-1,2,5,6-tetrahydropyridin-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 355F for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 1H), 8.49(br s, 1H), 8.44 (s, 1H), 7.69 (dd, 1H), 7.56 (d, 1H), 7.40 (d, 1H),7.24 (m, 1H), 7.13 (m, 3H), 6.98 (m, 1H), 6.94 (t, 1H), 6.86 (dd, 1H),6.36 (m, 1H), 6.24 (m, 2H), 3.84 (dd, 2H), 3.47 (t, 2H), 3.26 (m, 4H),2.99 (br s, 4H), 2.80 (m, 3H), 2.44 (m, 2H), 2.21 (m, 4H), 1.86 (m, 1H),1.73 (m, 2H), 1.62 (m, 2H), 1.26 (m, 5H), 1.17 (m, 2H).

Example 356 benzyl4-({[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenyl]amino}methyl)piperidine-1-carboxylateExample 356A benzyl4-((2-nitro-4-sulfamoylphenylamino)methyl)piperidine-1-carboxylate

The title compound was prepared as described in EXAMPLE 1F by replacing(tetrahydro-2H-pyran-4-yl)methanamine with benzyl4-(aminomethyl)piperidine-1-carboxylate.

Example 356B benzyl4-({[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenyl]amino}methyl)piperidine-1-carboxylate

The title compound was prepared as described in EXAMPLE 175F byreplacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 26C and EXAMPLE 356A,respectively. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 2H),8.63 (t, 1H), 8.58 (d, 1H), 7.79 (dd, 1H), 7.51 (d, 1H), 7.30-7.42 (m,8H), 7.16 (d, 1H), 7.10 (d, 1H), 7.03 (d, 2H), 6.86 (dd, 1H), 6.65 (dd,1H), 6.39 (s, 1H), 6.14 (d, 1H), 5.07 (s, 2H), 4.02 (d, 2H), 3.29-3.34(m, 2H), 3.03 (s, 4H), 2.70-2.88 (m, 4H), 2.08-2.23 (m, 6H), 1.94 (s,2H), 1.81-1.89 (m, 1H), 1.71 (d, 2H), 1.37 (t, 2H), 1.07-1.16 (m, 2H),0.92 (s, 6H).

Example 357N-{[3-(aminocarbonyl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamideExample 357A3-cyano-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide

To (tetrahydro-2H-pyran-4-yl)methanol (0.206 g) in tetrahydrofuran (5mL) was added sodium hydride (0.284 g) and the reaction stirred at roomtemperature for 20 minutes. The reaction was cooled to 0° C. and3-cyano-4-fluorobenzenesulfonamide (0.355 g) in tetrahydrofuran (2 mL)was added dropwise and the reaction was allowed to warm to roomtemperature. After 3 hours, the reaction was poured into water, madeacidic (pH=1) with 1N HCl and extracted with dichloromethane (2×75 mL).The organics were combined, washed with brine (50 mL), dried overmagnesium sulfate, filtered and concentrated to give the title compound.

Example 357B 5-sulfamoyl-2-((tetrahydro-2H-pyran-4-yl)methoxy)benzamide

A mixture of EXAMPLE 357A (0.455 g) in ethanol (3 mL) andtetrahydrofuran (1 mL) was added to hydrogen peroxide (30%, 2 mL)followed by NaOH (1.024 ml) and heated to 35° C. for 3 hours. Themixture was poured into dichloromethane (50 mL) and 1N aqueous HCl (25mL), upon which a precipitate formed. The title compound was extractedinto dichloromethane (3×50 mL). The organic layer contained a solidwhich was collected by filtration and dried to give the title compound.

Example 357CN-{[3-(aminocarbonyl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 357B for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz, CDCL3) δ10.35 (s, 1H), 8.80 (d, 1H), 8.35 (dd, 2H), 7.91 (d, 1H), 7.44 (d, 2H),7.39 (d, 1H), 7.34-7.29 (m, 1H), 7.22 (d, 2H), 7.07 (d, 1H), 6.99 (dd,1H), 6.93-6.87 (m, 2H), 6.58 (s, 1H), 6.48 (dd, 1H), 6.06 (d, 1H), 5.80(s, 1H), 4.05 (dd, 4H), 3.46 (dd, 2H), 3.03 (s, 4H), 2.73 (s, 2H), 2.19(m, 7H), 1.96 (s, 2H), 1.74 (m, 2H), 1.43 (m, 4H), 0.93 (s, 6H).

Example 3584-(4-{[4′-chloro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 339C for EXAMPLE 26Cand EXAMPLE 173C for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.11 (s, 1H), 8.54 (d, 1H), 8.19 (d, 1H), 7.78(dd, 1H), 7.71-7.74 (m, 2H), 7.44-7.54 (m, 7H), 7.36-7.38 (m, 2H),7.04-7.07 (m, 2H), 6.87 (dd, 1H), 6.63 (dd, J=8.7, 1.68 Hz, 1H), 6.36(s, 1H), 6.16 (d, 1H), 3.93 (dd, 2H), 3.75 (br s, 2H), 3.41 (s, 2H),3.01-3.07 (m, 6H), 2.66-2.68 (m, 2H), 2.30 (s, 4H), 1.77-1.80 (m, 2H),1.47-1.53 (m, 2H).

Example 3594-{4-[(5-tert-butyl-4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 341C for EXAMPLE 26Cand EXAMPLE 173C for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.11, (s, 1H), 8.53 (t, 1H), 8.19 (d, 1H), 7.76(dd, 1H), 7.53 (d, 1H), 7.36-7.44 (m, 8H), 7.19 (s, 1H), 7.04-7.07 (m,2H), 6.81 (dd, 1H), 6.63 (dd, 1H), 6.36 (s, 1H), 6.17 (d, 1H), 3.93 (dd,2H), 3.74-3.75 (m, 2H), 3.01-3.07 (m, 6H), 2.64-2.67 (m, 2H), 2.29 (s,4H), 1.99-2.03 (m, 4H), 1.77-1.80 (m, 2H), 1.65-1.67 (m, 2H), 1.28 (s,9H).

Example 3604-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1-methyl-1H-imidazol-5-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting(1-methyl-1H-imidazol-5-yl)methanamine for(3S,4R)-4-amino-1-benzylpiperidin-3-ol, hydrochloric acid in EXAMPLE187B. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 1H), 8.81 (t,1H), 8.59 (d, 1H), 7.83 (dd, 1H), 7.64 (s, 1H), 7.50 (d, 1H), 7.39-7.42(m, 2H), 7.33 (d, 2H), 7.16-7.17 (m, 2H), 7.03 (d, 2H), 6.98 (s, 1H),6.85 (dd, 1H), 6.63 (dd, 1H), 6.40 (s, 1H), 6.13 (d, 1H), 4.66 (d, 2H),3.64 (s, 3H), 3.02 (s, 4H), 2.72 (s, 2H), 2.12-2.16 (m, 6H), 1.94 (s,2H), 1.37 (t, 2H), 0.92 (s, 6H).

Example 3614-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylsulfonyl)phenyl]sulfonyl}benzamideExample 361A 4-(morpholinosulfonyl)benzenesulfonamide

This example was prepared by substituting4-(morpholinosulfonyl)benzene-1-sulfonyl chloride for EXAMPLE 66D inEXAMPLE 66E.

Example 361B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylsulfonyl)phenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 361A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 10.99 (s, 1H),7.76 (d, 2H), 7.57 (d, 1H), 7.46 (d, 2H), 7.35 (d, 2H), 7.28 (m, 2H),7.05 (d, 2H), 6.89 (d, 1H), 6.70 (dd, 1H), 6.57 (dd, 1H), 6.31 (m, 1H),6.21 (m, 1H), 3.60 (m, 4H), 2.97 (m, 4H), 2.79 (m, 4H), 2.72 (s, 2H),2.18 (m, 6H), 1.96 (s, 2H), 1.39 (t, 2H), 0.93 (s, 6H).

Example 3624-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamideExample 362A4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonamide

This example was prepared by substituting4-aminothiomorpholine-1,1-dioxide for (tetrahydropyran-4-yl)methylaminein EXAMPLE 1F.

Example 362B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 362A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.19 (s, 1H),11.17 (s, 1H), 9.64 (s, 1H), 8.55 (d, 1H), 7.86 (m, 1H), 7.78 (m, 1H),7.51 (d, 1H), 7.40 (m, 2H), 7.33 (d, 2H), 7.16 (s, 1H), 7.03 (d, 2H),6.86 (dd, 1H), 6.64 (dd, 1H), 6.39 (s, 1H), 6.13 (d, 1H), 3.50 (m, 4H),3.17 (m, 4H), 3.02 (m, 4H), 2.72 (s, 2H), 2.15 (m, 6H), 1.94 (s, 2H),1.37 (t, 2H), 0.91 (s, 6H).

Example 3634-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 363A tert-butyl cis-4-morpholinocyclohexylcarbamate

To a mixture of morpholine (4.08 ml) and tert-butyl4-oxocyclohexylcarbamate (10 g) stirred for 24 hours at room temperaturein titanium(IV) isopropoxide (27.5 ml), methanol (10 ml) was addedfollowed by careful addition of sodium borohydride (3.55 g). Thereaction mixture was quenched with water, extracted with ether (2×100mL), dried over magnesium sulfate, filtered and concentrated. The crudeproduct was purified by FC (silica gel 200 g, 30%-100% acetone/hexanes)providing two products, the title compound and trans4-morpholinocyclohexylcarbamate.

Example 363B cis-4-morpholinocyclohexanamine bis(2,2,2-trifluoroacetate)

This example was prepared by substituting EXAMPLE 363A for EXAMPLE 1A inEXAMPLE 1B.

Example 363C4-(cis-4-morpholinocyclohexylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting EXAMPLE 363B for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 363D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[cis-(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 363C for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz, pyridine-ds)δ 12.28 (s, 1H), 9.31 (d, 1H), 8.65 (d, 1H), 8.34 (dd, 1H), 8.17 (d,1H), 7.53-7.57 (m, 2H), 7.40-7.47 (m, 3H), 7.03-7.12 (m, 3H), 6.89 (d,1H), 6.72 (dd, 1H), 6.62 (s, 1H), 6.54 (d, 1H), 3.69-3.75 (m, 4H), 3.67(s, 1H), 3.00-3.07 (m, 4H), 2.75 (s, 2H), 2.41-2.47 (m, 4H), 2.24 (t,2H), 2.07-2.16 (m, 5H), 1.97 (s, 2H), 1.76-1.85 (m, 2H), 1.54-1.65 (m,6H), 1.38 (t, 2H), 0.93 (s, 6H).

Example 364N-{[5-bromo-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 26Cand EXAMPLE 329B for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.17 (s, 1H), 8.65 (d, 1H), 8.33 (s, 1H), 7.58(d, 1H), 7.35 (d, 2H), 7.24 (t, 1H), 7.07 (m, 3H), 6.89 (m, 1H), 6.67(dd, 1H), 6.27 (m, 3H), 4.29 (d, 2H), 3.88 (dd, 2H), 3.35 (m, 4H), 3.09(m, 4H), 2.88 (m, 2H), 2.34 (m, 2H), 2.17 (s, 2H), 2.06 (m, 1H), 1.98(m, 2H), 1.65 (m, 2H), 1.36 (m, 4H), 0.93 (s, 6H).

Example 3654-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-5-(1,3-thiazol-2-yl)pyridin-3-yl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 325B for EXAMPLE 329Bin EXAMPLE 331A. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.22 (s, 1H),9.76 (t, 1H), 9.12 (m, 1H), 8.50 (d, 1H), 8.26 (d, 1H), 8.02 (d, 1H),7.87 (d, 1H), 7.58 (d, 1H), 7.38 (d, 2H), 7.23 (t, 1H), 7.15 (d, 1H),7.08 (d, 2H), 6.96 (m, 1H), 6.74 (dd, 1H), 6.47 (d, 1H), 6.33 (s, 1H),6.22 (s, 1H), 3.86 (dd, 2H), 3.52 (t, 6H), 3.29 (m, 4H), 2.99 (m, 2H),2.74 (m, 2H), 2.18 (s, 2H), 2.01 (s, 2H), 1.88 (m, 1H), 1.62 (m, 2H),1.45 (t, 2H), 1.28 (m, 2H), 0.94 (s, 6H).

Example 3664-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamideExample 366A3-cyano-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide

3-Cyano-4-fluorobenzenesulfonamide (500 mg),(tetrahydropyran-4-yl)methylamine (288 mg), andN,N-diisopropylethylamine (1.3 mL) were heated at 80° C. intetrahydrofuran (15 mL) overnight. The mixture was diluted with ethylacetate, washed with NaHCO₃ solution and brine, and dried (Na₂SO₄),filtered and concentrated. The product was triturated from ethylacetate.

Example 366B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 26Cand EXAMPLE 366A for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.30 (s, 1H), 11.08 (m, 1H), 7.81 (d, 1H), 7.63(dd, 1H), 7.55 (d, 1H), 7.32 (m, 3H), 7.22 (d, 1H), 7.17 (m, 1H), 7.02(m, 3H), 6.79 (d, 1H), 6.71 (dd, 1H), 6.47 (d, 1H), 6.28 (m, 2H), 3.84(dd, 2H), 3.25 (t, 2H), 3.13 (t, 2H), 3.05 (m, 4H), 2.73 (s, 2H), 2.15(m, 6H), 1.95 (s, 2H), 1.82 (m, 1H), 1.59 (m, 2H), 1.38 (t, 2H), 1.20(m, 2H), 0.92 (s, 6H).

Example 3674-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 366A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.20 (s, 1H),10.99 (s, 1H), 7.94 (d, 1H), 7.74 (dd, 1H), 7.53 (d, 1H), 7.44 (d, 1H),7.41 (m, 1H), 7.33 (d, 2H), 7.21 (m, 2H), 7.04 (d, 2H), 6.89 (dd, 1H),6.82 (d, 1H), 6.66 (dd, 1H), 6.42 (s, 1H), 3.83 (dd, 2H), 3.25 (t, 2H),3.13 (t, 2H), 3.03 (m, 4H), 2.72 (s, 2H), 2.14 (m, 6H), 1.94 (s, 2H),1.83 (m, 1H), 1.57 (m, 2H), 1.37 (m, 2H), 1.21 (m, 2H), 0.92 (s, 6H).

Example 3684-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3,3-dimethylbutyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting 3,3-dimethylbutylamine for1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.

Example 3694-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1S)-1-(hydroxymethyl)-3-methylbutyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting L-leucinol for1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.

Example 3704-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}phenyl)sulfonyl]benzamide

This example was prepared by substituting(R)-(−)-tetrahydrofurfurylamine for1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.

Example 3714-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R)-1-(hydroxymethyl)-2-methylpropyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting D-valinol for1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.

Example 3724-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methoxyphenyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting 4-anisidine for1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.

Example 373N-[(4-{[2-(1,3-benzodioxol-5-yl)ethyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting2-benzo[1,3]dioxol-5-yl-ethylamine for1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.

Example 3744-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide

This example was prepared by substituting1-(3-amino-propyl)-pyrrolidin-2-one for1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.

Example 3754-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-hydroxyphenyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting 4-aminophenol for1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.

Example 376N-{[4-({2-[4-(aminosulfonyl)phenyl]ethyl}amino)-3-nitrophenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting4-(2-aminoethyl)benzenesulfonamide for1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.

Example 3774-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(1H-imidazol-1-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting 1-(3-aminopropyl)imidazole for1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.

Example 3784-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(1S)-1-phenylethyl]amino}phenyl)sulfonyl]benzamide

This example was prepared by substituting (S)-(−)-1-phenylethylamine for1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.

Example 379N-({2-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamideExample 379A2-chloro-5-fluoro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonamide

2-Chloro-4,5-difluorobenzenesulfonamide (0.683 g),(tetrahydro-2H-pyran-4-yl)methanamine (0.346 g),N,N-diisopropylethylamine (0.681 ml) and dioxane (10 ml) were heated at65° C. for 2.5 days. Additional (tetrahydro-2H-pyran-4-yl)methanamine(0.346 g) and N,N-diisopropylethylamine (0.681 ml) were added andheating was continued at 70° C. for 1.5 days. The reaction mixture wasconcentrated and column chromatographed on silica gel with 0-3% methanolin dichloromethane as eluent. The obtained solid was triturated withdichloromethane to give the title compound.

Example 379BN-({2-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 379A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 11.23 (s, 1H), 11.02 (s, 1H), 7.61 (m, 2H),7.44 (m, 2H), 7.33 (d, 2H), 7.30 (m, 1H), 7.03 (d, 2H), 6.95 (m, 1H),6.88 (m, 2H), 6.67 (dd, 1H), 6.44 (m, 1H), 6.09 (d, 1H), 3.82 (dd, 2H),3.22 (m, 2H), 3.03 (m, 6H), 2.72 (m, 2H), 2.14 (m, 6H), 1.94 (m, 2H),1.81 (m, 1H), 1.61 (m, 2H), 1.37 (t, 2H), 1.18 (m, 2H), 0.91 (s, 6H).

Example 3804-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]thio}-3-nitrophenyl)sulfonyl]benzamideExample 380A 4-(2-(2-methoxyethoxy)ethylthio)-3-nitrobenzenesulfonamide

In a 100 mL round-bottomed flask was added sodium hydride (0.6 g) intetrahydrofuran (10 ml) to give a suspension.2-(2-Methoxyethoxy)ethanethiol (1 g) was added slowly. After the mixturestirred for 30 minutes, 4-fluoro-3-nitrobenzenesulfonamide (1.616 g) in10 ml tetrahydrofuran was added slowly. After the mixture stirredovernight, water was added slowly, and ethyl acetate (20 ml×3) was usedto extract the product. The combined organic layers were dried overNa₂SO₄. After the mixture was filtered and concentrated, the crudeproduct was added to a silica gel column and purified eluting with 0-10%methanol in dichloromethane.

Example 380B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]thio}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 380A for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 10.99 (s, 1H),8.42 (s, 1H), 7.75 (d, 1H), 7.56 (d, 1H), 7.34 (m, 5H), 7.05 (d, 2H),6.90 (d, 1H), 6.69 (dd, 1H), 6.55 (dd, 1H), 6.30 (m, 1H), 6.17 (d, 1H),3.67 (t, 2H), 3.54 (m, 2H), 3.43 (m, 2H), 3.21 (m, 5H), 2.95 (m, 4H),2.71 (s, 2H), 2.17 (m, 6H), 1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 3814-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]thio}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 380A for EXAMPLE 1Fand EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.06 (s, 1H), 8.37 (d, 1H), 7.80 (dd, 1H), 7.61(d, 1H), 7.45 (d, 1H), 7.34 (d, 2H), 7.18 (t, 1H), 7.04 (m, 3H), 6.87(t, 1H), 6.60 (dd, 1H), 6.22 (m, 3H), 3.68 (t, 2H), 3.55 (m, 2H), 3.43(m, 2H), 3.22 (m, 5H), 2.94 (m, 4H), 2.72 (s, 2H), 2.16 (m, 6H), 1.95(s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 3824-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(methylsulfonyl)phenyl]sulfonyl}benzamide

This example was prepared by substituting4-(methylamino)-3-nitrobenzenesulfonamide for EXAMPLE 1F in EXAMPLE 177.¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 1H), 8.05 (m, 4H),7.51 (d, 1H), 7.38 (m, 4H), 7.14 (m, 1H), 7.04 (d, 2H), 6.85 (d, 1H),6.64 (dd, 1H), 6.40 (m, 1H), 6.17 (d, 1H), 3.27 (s, 3H), 3.05 (m, 4H),2.79 (m, 2H), 2.21 (m, 6H), 1.96 (s, 2H), 1.39 (t, 2H), 0.92 (s, 6H).

Example 3834-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(methylsulfonyl)phenyl]sulfonyl}benzamide

This example was prepared by substituting4-(methylamino)-3-nitrobenzenesulfonamide for EXAMPLE 1F and EXAMPLE 55Bfor EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ11.26 (s, 1H), 7.96 (m, 4H), 7.54 (d, 1H), 7.35 (d, 2H), 7.30 (m, 1H),7.18 (d, 1H), 7.05 (d, 2H), 6.97 (t, 1H), 6.70 (dd, 1H), 6.37 (d, 1H),6.30 (m, 2H), 3.25 (s, 3H), 3.08 (m, 4H), 2.84 (m, 2H), 2.26 (m, 6H),1.97 (s, 2H), 1.40 (t, 2H), 0.93 (s, 6H).

Example 3844-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamideExample 384A

The title compound was prepared as described in EXAMPLE 297A byreplacing (1,4-dioxan-2-yl)methanol with(2,2-dimethyltetrahydro-2H-pyran-4-yl)methanol.

Example 384B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

The title compound was prepared as described in EXAMPLE 175F byreplacing EXAMPLE 175E and EXAMPLE 1F with EXAMPLE 26C and EXAMPLE 384A,respectively. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 2H),8.38 (d, 1H), 8.05 (dd, 1H), 7.51 (d, 1H), 7.31-7.43 (m, 5H), 7.15 (d,1H), 7.04 (d, 2H), 6.85 (dd, 1H), 6.65 (dd, 1H), 6.40 (s, 1H), 6.15 (d,1H), 3.98-4.07 (m, 2H), 3.54-3.67 (m, 2H), 3.05 (s, 4H), 2.78 (s, 2H),2.09-2.31 (m, 7H), 1.95 (s, 2H), 1.56-1.68 (m, 2H), 1.38 (t, 2H),1.08-1.27 (m, 8H), 0.92 (s, 6H).

Example 3854-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indol-5-yloxy)benzamideExample 385A5-bromo-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 306C for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 329B.

Example 385B5-cyano-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 385A for EXAMPLE 329Bin EXAMPLE 333A.

Example 385C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 385B for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.10 (s, 1H),8.79 (s, 1H), 8.59 (s, 1H), 7.54 (d, 1H), 7.34-7.38 (m, 4H), 7.04-7.06(m, 3H), 6.79 (dd, 1H), 6.62 (dd, 1H), 6.35 (s, 1H), 6.17 (d, 1H), 4.28(d, 2H), 3.76-3.79 (m, 2H), 3.56-3.62 (m, 2H), 3.07 (br s, 4H),2.12-2.17 (m, 4H), 1.96 (s, 2H), 1.80-1.84 (m, 2H), 1.40 (t, 2H), 0.94(s, 6H).

Example 3864-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 26Cand EXAMPLE 335A for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.20 (s, 1H), 8.67 (d, 1H), 8.35 (d, 1H), 7.57(d, 1H), 7.36 (d, 2H), 7.26 (t, 1H), 7.11 (d, 1H), 7.05 (d, 2H), 6.90(t, 1H), 6.70 (dd, 1H), 6.31 (d, 1H), 6.30 (d, 1H), 6.27 (s, 1H), 4.30(d, 2H), 3.88 (dd, 2H), 3.35 (m, 2H), 3.12 (br s, 4H), 2.96 (br s, 2H),2.40 (br s, 4H), 2.16 (br m, 2H), 2.06 (m, 1H), 1.98 (s, 2H), 1.65 (d,2H), 1.41 (t, 2H), 1.36 (m, 2H), 0.93 (s, 6H).

Example 3874-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamideExample 387A 5,6-dichloropyridine-3-sulfonamide

This example was prepared by substituting5,6-dichloropyridine-3-sulfonyl chloride for5-bromo-6-chloropyridine-3-sulfonyl chloride in EXAMPLE 329A.

Example 387B5-chloro-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 387A for EXAMPLE 329Ain EXAMPLE 329B.

Example 387C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 26Cand EXAMPLE 387B for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.24 (s, 1H), 8.45 (d, 1H), 8.05 (d, 1H), 7.56(d, 1H), 7.36 (d, 2H), 7.28 (t, 1H), 7.15 (d, 1H), 7.05 (d, 2H), 6.95(t, 1H), 6.71 (dd, 1H), 6.39 (d, 1H), 6.30 (d, 1H), 6.27 (s, 1H), 4.26(d, 2H), 3.88 (dd, 2H), 3.35 (m, 2H), 3.09 (br s, 4H), 2.85 (br s, 2H),2.30 (br s, 4H), 2.15 (br m, 2H), 2.07 (m, 1H), 1.96 (s, 2H), 1.65 (d,2H), 1.41 (t, 2H), 1.35 (m, 2H), 0.93 (s, 6H).

Example 3884-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-5-yloxy)benzamideExample 388A 5-bromo-6-(2-morpholinoethoxy)pyridine-3-sulfonamide

This example was prepared by substituting 2-morpholinoethanol for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 329B.

Example 388B 5-cyano-6-(2-morpholinoethoxy)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 388A for EXAMPLE 329Bin EXAMPLE 335A.

Example 388C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting EXAMPLE 388B for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.09 (s, 1H),8.77 (s, 1H), 8.55 (s, 1H), 7.55 (d, 1H), 7.34-7.36 (m, 4H), 7.04-7.06(m, 3H), 6.78 (dd, 1H), 6.63 (d, 1H), 6.35 (s, 1H), 6.16 (s, 1H), 4.61(t, 2H), 3.58 (m, 4H), 3.05 (br s, 4H), 2.89 (br s, 4H), 2.65 (br s,4H), 2.32-2 (br s, 2H), 2.15 (br s, 2H), 1.96 (s, 2H), 1.39 (t, 2H),0.92 (s, 6H).

Example 3894-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]phenyl}sulfonyl)benzamideExample 389A 1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ol

Piperidin-4-ol (7.8 g) and dihydro-2H-pyran-4(3H)-one (5.0 g) weredissolved in titanium(IV) isopropoxide (30 mL) and the reaction wasstirred at room temperature overnight. Methanol (40 mL) was added andthe reaction was cooled to 0°. NaBH₄ (3.8 g) was added in severalportions over one hour. After two hours 1N aqueous NaOH was added,followed by ethyl acetate addition. After filtration through celite, thelayers were separated, the aqueous layer was extracted with ethylacetate, and the combined organic layers were dried over Na₂SO₄. Thecrude material was purified by column chromatography using CH₂Cl₂ with5-10% 7N NH₃ in methanol.

Example 389B3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-yloxy)benzenesulfonamide

EXAMPLE 389A (370 mg) was dissolved in tetrahydrofuran (10 mL), and 95%NaH (200 mg) was added. After stirring for 10 minutes,4-fluoro-3-nitrobenzenesulfonamide (420 mg) was added and the reactionwas stirred at room temperature overnight. The reaction was purified bycolumn chromatography using CH₂Cl₂ with 6-10% 7N NH₃ in methanol,followed by slurrying in diethyl ether and filtering off the solidproduct.

Example 389C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 389B for EXAMPLE 1F in EXAMPLE 1G, except here 5-7% methanol inCH₂Cl₂ was used for the chromatography. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.07 (br s, 1H), 8.27 (s, 1H), 7.92 (d, 1H),7.55 (d, 1H), 7.33 (m, 5H), 7.04 (m, 3H), 6.77 (dd, 1H), 6.58 (d, 1H),6.35 (s, 1H), 6.14 (s, 1H), 4.85 (s, 1H), 3.93 (dd, 2H), 3.27 (m, 4H),2.98 (br m, 7H), 2.72 (s, 2H), 2.16 (m, 6H), 2.04 (m, 2H), 1.95 (s, 2H),1.84 (m, 4H), 1.55 (m, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 3904-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)benzamideExample 390A 4-morpholinobut-2-yn-1-ol

To a mixture of morpholine (4.36 g) in toluene (15 mL) was added4-chlorobut-2-yn-1-ol (2.09 g) in toluene (5 mL). The mixture wasstirred at 85° C. for three hours. After cooling, the solid was filteredoff. The filtrate was subjected to vacuum distillation to give the titlecompound.

Example 390B 4-(4-morpholinobut-2-ynyloxy)-3-nitrobenzenesulfonamide

This example was prepared by substituting EXAMPLE 390A for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 279A.

Example 390C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 390B for EXAMPLE 1F inEXAMPLE 177. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.17 (s, 1H),8.40 (d, 1H), 8.11 (dd, 1H), 7.49-7.53 (m, 2H), 7.39-7.42 (m, 4H), 7.34(d, 2H), 7.17 (d, 1H), 7.04 (d, J=8.54 Hz, 2H), 6.85 (dd, 1H), 6.64 (dd,1H), 6.40 (s, 1H), 6.14 (d, 1H), 5.15 (s, 2H), 3.52-3.54 (m, 4H), 3.04(br s, 4H), 2.78 (br s, 2H), 2.37-2.39 (m, 4H), 2.12-2.20 (br s, 6H),1.95 (s, 2H), 1.38 (t, 2H), 0.92 (s, 6H).

Example 3914-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamideExample 391A6-((tetrahydro-2H-pyran-4-yl)methoxy)-5-((triisopropylsilyl)ethynyl)pyridine-3-sulfonamide

EXAMPLE 329B (0.176 g), bis(triphenylphosphine)palladium(II) chloride(0.176 g), copper(I) iodide (0.010 g), dimethylacetamide (2.5 ml) andtriethylamine (0.105 ml) were combined, flushed with nitrogen andstirred for 2 minutes. (Triisopropyl)acetylene (0.135 ml) was added andthe reaction mixture was flushed with nitrogen again, heated at 60° C.overnight, diluted with ethyl acetate, washed with water and brine,dried (MgSO₄), filtered, concentrated and chromatographed on silica gelwith 10-30% ethyl acetate in hexanes as the eluent to give the titlecompound.

Example 391B5-ethynyl-6-((tetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

EXAMPLE 391A (0.205 g) in tetrahydrofuran (3 ml) at ambient temperaturewas treated with tetrabutyl ammonium fluoride (1 M in tetrahydrofuran)(0.906 ml) and stirred at ambient temperature for 4 hours. Additionaltetrabutyl ammonium fluoride (1 M in tetrahydrofuran) (1.8 mL) was addedand the mixture was heated at 40° C. for 45 minutes. Solid tetrabutylammonium fluoride (0.253 g) was added and heating was continued for 30minutes. The reaction mixture was concentrated and then chromatographedon silica gel using 0-2% methanol in dichloromethane as the eluent togive the title compound.

Example 391C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 26Cand EXAMPLE 391B for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ ppm 11.23 (s, 1H), 8.50 (d, 1H), 8.09 (d, 1H),7.56 (d, 1H), 7.34 (m, 2H), 7.28 (m, 1H), 7.18 (d, 1H), 7.04 (m, 2H),6.98 (t, 1H), 6.70 (dd, 1H), 6.44 (d, 1H), 6.27 (m, 2H), 4.55 (s, 1H),4.25 (d, 2H), 3.87 (dd, 2H), 3.34 (m, 2H), 3.06 (m, 4H), 2.81 (m, 1H),2.20 (m, 6H), 2.04 (m, 1H), 1.96 (m, 2H), 1.65 (dd, 2H), 1.35 (m, 5H),0.92 (m, 6H).

Example 3924-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 26Cand EXAMPLE 388B for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.15 (s, 1H), 10.99 (s, 1H), 8.64 (d, 1H), 8.33(d, 1H), 7.58 (d, 1H), 7.35 (d, 2H), 7.24 (m, 1H), 7.07 (m, 3H), 6.89(m, 1H), 6.66 (dd, 1H), 6.26 (m, 3H), 4.59 (t, 2H), 3.58 (m, 4H), 3.05(m, 4H), 2.87 (m, 4H), 2.62 (m, 4H), 2.24 (m, 6H), 1.98 (m, 2H), 1.40(t, 2H), 0.93 (s, 6H).

Example 3934-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 55B for EXAMPLE 26Cand EXAMPLE 385B for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.17 (s, 1H), 8.66 (s, 1H), 8.36 (s, 1H), 7.58(d, 1H), 7.36 (d, 2H), 7.25 (s, 1H), 7.07 (m, 3H), 6.89 (m, 1H), 6.68(m, 1H), 6.27 (m, 3H), 4.60 (s, 1H), 4.54 (s, 1H), 3.78 (m, 2H), 3.60(m, 2H), 3.33 (m, 2H), 3.09 (m, 4H), 2.92 (m, 2H), 2.36 (m, 2H), 2.16(m, 2H), 1.97 (s, 2H), 1.87 (m, 4H), 1.40 (t, 2H), 0.93 (s, 6H).

Example 3944-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-hydroxy-4-methoxyphenyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide

This example was prepared by substituting 5-amino-2-methoxyphenol for1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 187A for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.

Example 3954-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-dihydro-1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

EXAMPLE 103 (676 mg) and NaCNBH₃ (49 mg) were combined in acetic acid(10 mL) and stirred at room temperature overnight. The reaction wasdiluted with water and extracted with 95/5 CH₂Cl₂/methanol. The organiclayer was concentrated and the crude material was purified bypreparative HPLC using a C18 column, 250×50 mm, 10μ, and eluting with agradient of 20-100% CH₃CN vs. 0.1% trifluoroacetic acid in water, givingthe title compound as a bistrifluoroacetate salt. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.57 (br s, 1H), 9.70, 9.50 (both v br s, total2H), 8.57 (d, 1H), 8.20 (br d, 1H), 7.85 (dd, 1H), 7.50 (d, 1H), 7.40(d, 2H), 7.26 (d, 1H), 7.10 (d, 2H), 6.82 (dd, 1H), 6.75 (dd, 1H), 6.40(d, 1H), 6.27 (d, 1H), 5.94 (d, 1H), 4.00, 3.70 (both v br m, total 8H),3.55 (v br m, 3H), 3.42 (t, 2H), 3.37 (v br m, 1H), 3.10 (br m, 2H),2.80 (m, 6H), 2.20 (br m, 4H), 2.03 (s, 2H), 1.82 (br m, 2H), 1.46 (t,2H), 0.96 (s, 6H).

Example 3964-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(pyridin-3-ylamino)benzamideExample 396A Methyl4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(pyridin-3-ylamino)benzoate

A solution of EXAMPLE 18E (500 mg), cesium carbonate (429 mg), palladium(II) acetate (21 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl(58.5 mg) and toluene (6.4 mL) was degassed with N₂. The mixture wasstirred at 115° C. for 5 minutes. After cooling to room temperature,pyridin-3-amine (106 mg) was added and the reaction mixture was degassedagain with N₂ and was stirred at 115° C. for 45 minutes. The mixture wascooled to room temperature, diluted with ethyl acetate and was washedwith H₂O, brine, dried (MgSO₄), filtered and concentrated. The crudeproduct was purified by flash chromatography on silica gel, eluting withCH₂Cl_(2/1)% methanol to afford the title compound.

Example 396B4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(pyridin-3-ylamino)benzoicacid, 2 Hydrochloric Acid

This example was prepared by substituting EXAMPLE 396A for EXAMPLE 224Cin EXAMPLE 224D.

Example 396C4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonyl)-2-(pyridin-3-ylamino)benzamide

This example was prepared by substituting EXAMPLE 396B for EXAMPLE 26Cand EXAMPLE 21A for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 11.32-11.40 (br s, 1H), 9.21-9.39 (br s, 1H),8.51 (d, 1H), 8.33 (d, 1H), 8.09 (dd, 1H), 7.98-8.07 (m, 1H), 7.94 (dd,1H), 7.81 (d, 1H), 7.52-7.58 (m, 1H), 7.36 (d, 2H), 7.24-7.30 (m, 1H),7.15 (d, 1H), 7.08 (d, 2H), 6.53 (d, 1H), 6.33 (dd, 1H), 3.81-3.96 (brs, 2H), 3.02-3.12 (br s, 6H), 2.67-2.80 (m, 5H), 2.07-2.32 (m, 8H), 1.98(s, 3H), 1.70-1.85 (br s, 1H), 1.41 (t, 3H), 0.95 (s, 6H).

Example 3974-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(pyridin-3-ylamino)benzamide

This example was prepared by substituting EXAMPLE 396B for EXAMPLE 26Cand EXAMPLE 173C for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 9.10-9.33 (br s, 1H), 8.53 (d, 1H), 8.36 (d,1H), 8.12 (dd, 1H), 8.00-8.07 (m, 1H), 7.96 (dd, 1H), 7.80 (d, 1H),7.53-7.59 (m, 1H), 7.38 (d, 2H), 7.25-7.31 (m, 1H), 7.20 (d, 1H), 7.09(d, 2H), 6.53 (s, 1H), 6.36 (m, 1H), 4.28-4.75 (br s, 1H), 3.90-4.09 (m,8H), 3.51-3.61 (m, 2H), 3.35 (m, 8H), 3.01-3.18 (br s, 4H), 2.15-2.26(m, 1H), 1.88-2.09 (m, 5H), 1.56-1.86 (m, 4H), 1.44 (t, 2H), 0.96 (s,6H).

Example 3984-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(pyridin-3-yloxy)benzamideExample 398A 4-Fluoro-2-(pyridin-3-yloxy)-benzoic acid methyl ester

This example was prepared by substituting methyl 2,4-difluorobenzoatefor ethyl 2,4-difluorobenzote and 3-hydroxypyridine for5-hydroxyindazole in EXAMPLE 20A.

Example 398B4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-(pyridin-3-yloxy)-benzoicacid methyl ester

This example was prepared by substituting EXAMPLE 398A for EXAMPLE 20Ain EXAMPLE 20D.

Example 398C4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-(pyridin-3-yloxy)-benzoicacid

This example was prepared by substituting EXAMPLE 398B for EXAMPLE 1D inEXAMPLE 1E.

Example 398D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(pyridin-3-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 398C for EXAMPLE 1Eand EXAMPLE 173C for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.36 (d, 1H), 8.11 (t, 1H), 8.08 (t, 2H), 7.70(dd, 1H), 7.60 (d, 1H), 7.37 (d, 2H), 7.15 (dd, 1H), 7.10-7.03 (m, 3H),7.00 (dd, 1H), 6.73 (dd, 1H), 6.43 (d, 1H), 3.99-3.93 (m, 3H), 3.86 (m,1H), 3.13 (m, 6H), 2.78 (br s, 2H), 2.30-2.05 (m, 10H), 1.98 (br s, 2H),1.92-1.67 (m, 6H), 1.57 (m, 2H), 1.41 (t, 2H), 0.94 (s, 6H).

Example 3994-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1,2,3,4-tetrahydroisoquinolin-5-yloxy)benzamideExample 399A tert-butyl5-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

A mixture of 1,2,3,4-tetrahydroisoquinolin-5-ol hydrochloric acid (1.0g), di-tert-butyl dicarbonate (1.27 g) and 1.0 N NaOH (14.5 mL) indioxane (20 mL) was stirred at room temperature for 16 hours. Thereaction mixture was partitioned between water and ethyl acetate. Theaqueous layer was neutralized with 5% HCl. The combined organic layerswere washed with brine, dried (MgSO₄), filtered, and concentrated. Theresidue was purified by flash chromatography on silica gel to give thetitle compound.

Example 399B tert-butyl5-(2-(ethoxycarbonyl)-5-fluorophenoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate

This example was prepared by substituting EXAMPLE 399A for5-hydroxyindazole in EXAMPLE 20A.

Example 399C tert-butyl5-(5-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(ethoxycarbonyl)phenoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate

This example was prepared by substituting EXAMPLE 399B for EXAMPLE 20Ain EXAMPLE 20D.

Example 399D2-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

This example was prepared by substituting EXAMPLE 399C for EXAMPLE 1D inEXAMPLE 1E.

Example 399E2-(2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-5-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoic3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)benzenesulfonicanhydride

This example was prepared by substituting EXAMPLE 399D for EXAMPLE 26Cin EXAMPLE 177.

Example 399F4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1,2,3,4-tetrahydroisoquinolin-5-yloxy)benzamide

A mixture of EXAMPLE 399E (0.058 g) and trifluoroacetic acid (1 mL) indichloromethane (10 mL) was stirred for 2 hours. The solvent wasremoved, and the residue was taken into ethyl acetate. It was thenwashed with saturated NaHCO₃, brine, dried over MgSO₄, filtered, andconcentrated to give the title compound. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 8.36 (t, 1H), 8.27 (d, 1H), 7.65 (d, 1H), 7.36(d, 2H), 7.07 (d, 2H) 6.93-6.97 (m, 2H), 6.73 (d, 1H), 6.69 (dd, 1H),6.33 (d, 1H), 6.26 (d, 1H), 4.19 (s, 2H), 3.85 (dd, 2H), 3.05-3.09 (m,6H), 2.77 (s, 2H), 2.17-2.24 (m, 6H), 1.98-1.99 (m, 2H), 1.60-1.63 (m,2H0, 1.41 (t, 2H), 0.94 (s, 6H).

Example 4004-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 400A 4-Hydroxy-indazole-1-carboxylic acid tert-butyl ester and4-hydroxy-indazole-2-carboxylic acid tert-butyl ester

4-Hydroxyindazole (3.94 g) was added to tetrahydrofuran (250 mL) andcooled to 0° C. using an ice bath. Sodium hydride (60% dispersion inmineral oil, 1.23 g) was added, and the mixture was stirred at 0° C. forfive minutes. The mixture was allowed to warm to room temperature andstirred for an additional 20 minutes. The mixture was again cooled to 0°C. using an ice bath, and tert-butyldimethylchlorosilane (4.65 g) wasadded. The mixture was allowed to warm to room temperature and stirredfor 16 hours. Solvent volume was reduced under vacuum, the residuevacuum filtered over a pad of silica gel and washed with ethyl acetate,and the solvent was removed under vacuum. To the residue was addedacetonitrile (200 mL), di-tert-butyl dicarbonate (7.06 g), and4-(dimethylamino)pyridine (0.359 g). The mixture was stirred at roomtemperature for three hours, and the solvent was removed under vacuum.To the residue was added tetrahydrofuran (200 mL) and tetrabutylammoniumfluoride (1M in tetrahydrofuran, 82 mL). The mixture was stirred at roomtemperature for four days, the solvent removed under vacuum, and theresidue taken up in ethyl acetate. The mixture was extracted withsaturated aqueous ammonium chloride, extracted with brine, and dried onanhydrous sodium sulfate. The mixture was vacuum filtered over silicagel, and the solvent removed under vacuum to give a mixture of the twoproducts, which was used in the next step without further purification.

Example 400B 4-Fluoro-2-(1H-indazol-4-yloxy)-benzoic acid methyl ester

EXAMPLE 400A (5.56 g) was added to diglyme (200 mL), and potassiumtert-butoxide (1M in tetrahydrofuran, 30.8 mL) was added. The mixturewas mixed at room temperature for 15 minutes, methyl2,4-difluorobenzoate was added, and the mixture was heated at 115° C.for 16 hours. The mixture was cooled, the solvent was removed undervacuum, the residue was taken up in dichloromethane (100 mL), andtrifluoroacetic acid (22.6 mL) was added. The mixture was stirred atroom temperature for 16 hours, the solvent was removed under vacuum, theresidue was taken up in ethyl acetate and washed with a saturatedaqueous sodium bicarbonate mixture, and the organic layer was dried withanhydrous sodium sulfate. The material was purified by flash columnchromatography on silica gel using 30% ethyl acetate (in hexanes)increasing to 40% ethyl acetate (in hexanes).

Example 400C 2-(1H-Indazol-4-yloxy)-4-piperazin-1-yl-benzoic acid methylester

EXAMPLE 400B (2.00 g) and piperazine (2.71 g) were added todimethylsulfoxide (60 mL) and heated to 100° C. for one hour. Themixture was cooled, added to dichloromethane, washed with water twice,washed with a saturated aqueous sodium bicarbonate mixture, and dried onanhydrous sodium sulfate. After filtration, the solvent was removedunder vacuum.

Example 400D4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-(1H-indazol-4-yloxy)-benzoicacid methyl ester

This example was prepared by substituting EXAMPLE 218A for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 400C for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 400E4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-(1H-indazol-4-yloxy)-benzoicacid

This example was prepared by substituting EXAMPLE 400D for EXAMPLE 1D inEXAMPLE 1E.

Example 400F4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 400E for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 13.09 (s, 1H), 8.56(t, 1H), 8.38 (d, 1H), 7.80 (s, 1H), 7.56 (dd, 1H), 7.53 (d, 1H), 7.36(d, 2H), 7.16-7.05 (m, 4H), 6.99 (d, 1H), 6.80 (dd, 1H), 6.52 (d, 1H),6.19 (dd, 1H), 3.87 (dd, 2H), 3.25-3.12 (m, 6H), 2.78 (m, 2H), 2.30-2.16(m, 6H), 1.97 (br s, 2H), 1.90 (m, 1H), 1.63 (m, 2H), 1.53 (m, 1H), 1.40(t, 2H), 1.29 (m, 3H), 0.94 (s, 6H).

Example 4014-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamideExample 401AN-[(4-chloro-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 400E for EXAMPLE 1Eand 4-chloro-3-nitrobenzenesulfonamide for EXAMPLE 1F in EXAMPLE 1G. ¹HNMR (300 MHz, dimethylsulfoxide-d₆) δ 13.04 (s, 1H), 8.17 (br s, 1H),7.75 (s, 1H), 7.73 (d, 1H), 7.66-7.61 (m, 2H), 7.38 (d, 2H), 7.11-7.01(m, 4H), 6.79 (dd, 1H), 6.54 (d, 1H), 6.10 (dd, 1H), 3.38-3.05 (m, 8H),2.73 (br s, 2H), 2.19 (m, 2H), 2.00 (br s, 2H), 1.44 (t, 2H), 0.95 (s,6H).

Example 401B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 173B for1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 401A for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 13.05 (br s, 1H), 8.35 (d, 1H), 8.13 (d, 1H),7.78 (s, 1H), 7.61-7.52 (m, 2H), 7.35 (d, 2H), 7.11-7.03 (m, 4H), 6.98(d, 1H), 6.77 (dd, 1H), 6.48 (d, 1H), 6.18 (m, 1H), 3.69-3.52 (m, 4H),3.12 (m, 6H), 2.76 (br s, 2H), 2.67 (m, 4H), 2.28-2.16 (m, 6H),2.09-2.01 (m, 2H), 1.97 (br s, 2H), 1.95 (m, 2H), 1.50-1.38 (m, 6H),0.93 (s, 6H).

Example 402

Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substitutingtrans-4-morpholin-4-yl-cyclohexylamine for1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 401A for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 13.02 (br s, 1H), 8.35 (d, 1H), 8.12 (m, 1H),7.75 (s, 1H), 7.65-7.55 (m, 2H), 7.35 (d, 2H), 7.10-7.03 (m, 4H), 6.97(m, 1H), 6.76 (dd, 1H), 6.44 (m, 1H), 6.17 (t, 1H), 3.95 (m, 2H), 3.77(m, 1H), 3.62 (m, 1H), 3.10 (m, 6H), 2.75 (br s, 2H), 2.28-2.14 (m, 8H),2.06 (m, 2H), 1.97 (br s, 2H), 1.85 (m, 2H), 1.71 (m, 2H), 1.55 (m, 4H),1.40 (t, 2H), 0.93 (s, 6H).

Example 4032-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 403A

methy 4-fluoro-2-(3-fluoro-2-nitrophenoxy)benzoate

To a solution of methyl 4-fluoro-2-hydroxybenzoate (3.0 g) intetrahydrofuran (65 mL) was added potassium t-butoxide (1.979 g) portionwise. The resulting solution was stirred at ambient temperature for 30minutes and a solution of 1,3-difluoro-2-nitrobenzene (2.338 g) intetrahydrofuran (15 mL) was added dropwise. After 1 hour, the reactionwas heated at reflux for 18 hours. The reaction was quenched with water(10 mL), diluted with brine (75 mL) and extracted with methylenechloride (2×75 mL). The crude product was isolated by concentration andpurified on silica gel, eluted with a 10, 20, 50% ethyl acetate inhexane step gradient to provide the title compound.

Example 403B methyl2(3-(bis(4-methoxyphenyl)methylamino)-2-mitrophenoxy)-4-fluorobenzoate

To a solution of EXAMPLE 403A (3.82 g) andbis(4-methoxyphenyl)methanamine (4.51 g) in N-methyl-2-pyrrolidinone (65mL) was added N-ethyl-N-isopropylpropan-2-amine (4.30 mL) and themixture was heated at 100° C. for 24 hours. The crude product, isolatedby concentration, was purified on silica gel, and was eluted with a 10,25, and 65% ethyl acetate in hexane step gradient to provide the titlecompound.

Example 403C methyl2-(2-amino-3-(bis(4-methoxyphenyl)methylamino)phenoxy)-4-fluorobenzoate

To a solution of EXAMPLE 403B (2.76 g) in tetrahydrofuran (125 mL) in astainless steel pressure bottle was added nickel catalyst (2.76 g). Themixture was stirred for 1 hour under hydrogen at 30 psi and ambienttemperature. The mixture was filtered though a nylon membrane to removethe catalyst, and concentrated to give the product.

Example 403D methyl2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-fluorobenzoate

To a solution EXAMPLE 403C (1.25 g) in triethyl orthoformate (30 mL) wasadded concentrated hydrochloric acid (0.75 mL). The mixture was stirredfor 18 hours, quenched by the slow addition of 50% saturated aqueoussodium carbonate solution (100 mL) and extracted with ethyl acetate(2×100 mL). The crude product was isolated by concentration and purifiedon silica gel, and was eluted with a 25, 50, and 70% ethyl acetate inhexane step gradient to provide title compound.

Example 403E methyl2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(piperazin-1-yl)benzoate

A solution of EXAMPLE 403D (500 mg), and piperazine (420 mg) indimethylsulfoxide (9 mL) was heated at 100° C. for 3 hours. The crudeproduct was isolated by concentration and, following an aqueous work up,it was purified on silica gel, and was eluted with a 5 and 10% methanolin methylene chloride step gradient to provide the title compound.

Example 403F methyl2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoate

To a solution of EXAMPLE 403E (430 mg) and EXAMPLE 218A (259 mg) indichloromethane (13 mL) was added sodium triacetoxyborohydride (323 mg)portionwise. After stirring 42 hours, the reaction was quenched slowlywith saturated aqueous sodium bicarbonate solution (80 mL) and extractedwith methylene chloride (2×70 mL). The crude product was isolated byconcentration and purified on silica gel, and was eluted with a 0, 2,10% methanol in methylene chloride step gradient to provide the titlecompound.

Example 403G2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)benzoicacid

To a solution of EXAMPLE 403F (545 mg) in a mixture of methanol (7.50mL) and tetrahydrofuran (7.50 mL) was added a solution of sodiumhydroxide (269 mg) in water (3.0 mL). The reaction mixture was heated at50° C. for 18 hours and then concentrated. The residue was mixed withwater (100 mL) and the pH was adjusted to ca. 7 with 1M aqueoushydrochloric acid. The mixture was extracted with 10% methanol inmethylene chloride (10×50 mL), and the combined organic layers wereconcentrated to provide the title compound.

Example 403H2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)benzamide

To a solution of EXAMPLE 403G (200 mg), EXAMPLE 1F (99 mg),triethylamine (0.122 mL), N,N-dimethylpyridin-4-amine (77 mg) in amixture of dichloromethane (8 mL) and N,N-dimethylformamide (1 mL) wasadded N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloric acid (96 mg). The reaction mixture was stirred 18 hours andthen concentrated. The crude product was purified on silica gel elutedwith an 80 and 100% ethyl acetate in hexane step gradient to provide thetitle compound.

Example 403I2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

A solution of EXAMPLE 403H (174 mg) and dichloromethane (25 mL) wascooled in an ice bath and 2,2,2-trifluoroacetic acid (25 mL) was addedslowly dropwise. The reaction mixture was stirred 30 minutes undernitrogen and the ice bath was removed. The reaction was stirred 18 hoursand then concentrated. The crude product was purified by reverse phasechromatography with ammonium acetate buffer in acetonitrile to give thetitle compound. ¹H NMR (400 MHz, pyridine-d₅) δ 9.30 (d, 1H), 8.69 (t,1H), 8.59 (s, 1H), 8.42 (dd, 1H), 7.99 (d, 1H), 7.53 (d, 1H), 7.43 (d,2H), 7.26 (m, 1H), 7.18 (m, 1H), 7.06 (d, 2H), 6.94 (d, 1H), 6.72-6.66(m, 2H), 5.53 (m, 2H), 3.98 (m, 2H), 3.32 (m, 2H), 3.18 (t, 2H), 2.03(m, 4H), 2.76 (s, 2H), 2.25 (m, 2H), 2.13 (m, 4H), 1.97 (s, 2H), 1.83(m, 1H), 1.60 (m, 2H), 1.40-1.29 (m, 4H), 0.94 (s, 6H).

Example 404N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamideExample 404A5-chloro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 387A for EXAMPLE329A and EXAMPLE 306C for (tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE329B.

Example 404BN-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 404A for EXAMPLE1F and EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 13.09 (s, 1H), 8.27 (d, 1H), 7.88 (d, 1H), 7.80(s, 1H), 7.60 (d, 1H), 7.37 (d, 2H), 7.03-7.10 (m, 4H), 6.79 (dd, 1H),6.53 (d, 1H), 6.13 (d, 1H), 4.50 (d, 2H), 3.76-3.81 (m, 2H), 3.57-3.63(m, 2H), 3.04 (br s, 4H), 2.84 (br s, 2H), 2.18 (m, 2H), 1.82-1.92 (m,4H), 1.42 (t, 2H), 0.94 (s, 6H).

Example 405N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 404A for EXAMPLE1F and EXAMPLE 55B for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.21 (s, 1H), 8.43 (d, 1H), 8.06 (d, 1H), 7.55(d, 1H), 7.34 (d, 2H), 7.27 (t, 1H), 7.13 (d, 1H), 7.04 (d, 2H), 6.93(t, 1H), 6.69 (dd, 1H), 6.36 (d, 1H), 6.28 (d, 1H), 6.26 (d, 1H), 4.51(d, 2H), 3.73-3.79 (m, 2H), 3.55-3.61 (m, 2H), 3.08 (br s, 4H), 2.86 (brs, 2H), 2.31 (br s, 2H), 2.18 (m, 2H), 1.95 (s, 2H), 1.79-1.90 (m, 4H),1.36 (t, 2H), 0.92 (s, 6H).

Example 4064-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 385B for EXAMPLE1F and EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 13.03 (s, 1H), 8.48 (d, 1H), 8.17 (s, 1H), 7.74(s, 1H), 7.63 (d, 1H), 7.37 (d, 2H), 7.00-7.08 (m, 4H), 6.77 (dd, 1H),6.51 (s, 1H), 6.07 (d, 1H), 4.55 (d, 2H), 3.77-3.81 (m, 2H), 3.58-3.63(m, 2H), 3.20 (br s, 4H), 2.19 (br s, 2H), 1.99 (s, 2H), 1.85-1.92 (m,4H), 1.42 (t, 2H), 0.94 (s, 6H).

Example 4072-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamideExample 407A (R)-tert-butyl1-(2,2-difluoroethyl)pyrrolidin-3-ylcarbamate

To a solution of (R)-tert-butyl pyrrolidin-3-ylcarbamate (500 mg),1,1-difluoro-2-iodoethane (618 mg) in N,N-dimethylformamide (6 mL) wasadded N-ethyl-N-isopropylpropan-2-amine (1.403 mL) and the reactionstirred for 72 hours at 70° C. The reaction mixture was concentrated andthe crude product was purified on a silica gel and was eluted with a 0,2, and 5% methanol in methylene chloride step gradient to provide thetitle compound.

Example 407B (R)-1-(2,2-difluoroethyl)pyrrolidin-3-amine

To a solution of EXAMPLE 407A (525 mg) in a mixture of dichloromethane(3 mL) and methanol (2.0 mL) was added hydrogen chloride, 4M in dioxane(5.24 mL). The reaction was stirred for 3 hours, and concentrated toprovide the title compound.

Example 407C(R)-4-(1-(2,2-difluoroethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide

To a solution of EXAMPLE 407B (468 mg) in tetrahydrofuran (20 mL),N-ethyl-N-isopropylpropan-2-amine (2.193 mL) and N,N-dimethylformamide(2 mL) was added 4-fluoro-3-nitrobenzenesulfonamide (473 mg) and thereaction mixture was stirred 72 hours. The crude product was isolated byconcentration and was purified on silica gel, and was eluted with a 0.5,2.5, and 5% methanol in methylene chloride step gradient to obtain thetitle compound.

Example 407D(R)-2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-nitrophenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 407C for EXAMPLE1F in EXAMPLE 403H.

Example 407E2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 407D for EXAMPLE403H in EXAMPLE 4031. ¹H NMR (400 MHz, pyridine-d₅) δ 9.26 (d, 1H),8.60-8.55 (m, 2H), 8.39 (m, 1H), 7.99 (d, 1H), 7.53 (d, 1H), 7.43 (d,2H), 7.25 (m, 1H), 7.17 (m, 1H), 7.06 (d, 2H), 6.86 (d, 1H), 6.72-6.69(m, 2H), 6.00-6.33 (m, 1H), 5.27 (m, 2H), 4.09 (m, 1H), 3.03 (m, 4H),2.96-2.86 (m, 4H), 2.81-2.74 (m, 3H), 2.48 (m, 1H), 2.26 (m, 3H), 2.13(m, 4H), 1.97 (s, 2H), 1.67 (m, 1H), 1.38 (t, 2H), 0.94 (s, 6H).

Example 4082-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamideExample 408A2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)-3-nitrophenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 306D for EXAMPLE1F in EXAMPLE 403H.

Example 408B2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 408A for EXAMPLE403H in EXAMPLE 4031. ¹H NMR (400 MHz, pyridine-d₅) δ 9.01 (d, 1H), 8.57(m, 2H), 7.99 (d, 1H), 7.53 (d, 1H), 7.44 (d, 2H), 7.25 (m, 1H), 7.21(m, 1H), 7.12 (d, 1H), 7.07 (d, 2H), 6.73-6.70 (m, 2H), 5.35 (m, 2H),4.36 (s, 1H), 4.31 (s, 1H), 3.88 (m, 2H), 3.78 (m, 2H), 3.05 (m, 4H),2.77 (s, 2H), 2.26 (m, 2H), 2.15 (m, 4H), 2.07-192 (m, 6H), 1.39 (t,2H), 0.94 (s, 6H).

Example 4094-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamideExample 409A (4-fluorotetrahydro-2H-pyran-4-yl)methyl methanesulfonate

A mixture of EXAMPLE 306C (1.4 g), methanesulfonyl chloride (1.054 mL),triethylamine (2.99 mL), and 4-(dimethylamino)pyridine (0.051 g) inCH₂Cl₂ (20 mL) was stirred at 0° C. for 2 hours, concentrated andchromatographed on silica gel with 30% ethyl acetate in hexanes aseluent to give the product.

Example 409B2-((4-fluorotetrahydro-2H-pyran-4-yl)methyl)isoindoline-1,3-dione

A mixture of EXAMPLE 409A (1.8 g) and potassium phthalimide (2.356 g) inN,N-dimethylformamide (30 mL) was heated at 150° C. overnight, dilutedwith ethyl acetate, washed with water and brine, dried (MgSO₄),filtered, concentrated and chromatographed on silica gel with 30% ethylacetate in hexanes as eluent to give the product.

Example 409C (4-fluorotetrahydro-2H-pyran-4-yl)methanamine

A mixture of EXAMPLE 409B (1.4 g) and hydrazine (1.548 mL) in ethanol(40 mL) was heated at 70° C. overnight, cooled to room temperature,slurried with CH₂Cl₂ (200 mL) and the solid removed by filtration. Thefiltrate was concentrated and chromatographed on silica gel with 100:5:1ethyl acetate/methanol/NH₄OH as eluent to give the product.

Example 409D4-((4-fluorotetrahydro-2H-pyran-4-yl)methylamino)-3-nitrobenzenesulfonamide

A mixture of 4-fluoro-3-nitrobenzenesulfonamide (0.44 g), EXAMPLE 409C(0.266 g), and triethylamine (1.11 mL) in tetrahydrofuran (10 mL) washeated at 70° C. overnight, diluted with ethyl acetate, washed withwater and brine, dried (MgSO₄), filtered, concentrated andchromatographed on silica gel with 50% ethyl acetate in hexanes aseluent to give the product.

Example 409E4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 409D for EXAMPLE1F and EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 13.09 (s, 1H), 8.59 (t, 1H), 8.37 (d, 1H), 7.80(s, 1H), 7.59 (dd, 1H), 7.37 (d, 2H), 7.04-7.13 (m, 5H), 6.79 (dd, 1H),6.51 (d, 1H), 6.18 (d, 1H), 3.70-3.79 (m, 4H), 3.50-3.56 (m, 2H), 3.15(br s, 4H), 2.78 (br s, 2H), 2.32 (br s, 4H), 2.17 (br s, 2H), 1.97 (s,2H), 1.75-1.83 (m, 4H), 1.40 (t, 2H), 0.93 (s, 6H).

Example 4104-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamideExample 410A 5-nitro-3-(trifluoromethyl)pyridin-2-ol

3-(Trifluoromethyl)pyridin-2-ol (2.3 g) was added to concentratedsulfuric acid (15 mL) at 0° C. The mixture was stirred at 0° C. for 5minutes. To this solution was added nitric acid (fuming) (6 mL) dropwiseover 5 minutes. The reaction mixture was stirred at room temperature for2 hours, and was heated at 50° C. for 3 hours. After cooling, thereaction mixture was poured into ice (200 g), and the mixture wasextracted with ethyl acetate three times. The combined organic layerswere washed with brine, dried over MgSO₄, filtered, and concentratedunder reduced pressure to give the title compound.

Example 410B 2-chloro-5-nitro-3-(trifluoromethyl)pyridine

A mixture of EXAMPLE 410A (1.69 g), phosphorus pentachloride (2.03 g),and phosphoryl trichloride (0.97 mL) was heated at 90° C. for 3 hours.After cooling, the reaction mixture was poured into ice, and extractedwith ethyl acetate three times. The extract was washed with brine, driedover MgSO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by flash column chromatography on silica geleluting with 1:9 ethyl acetate\hexanes to give the title compound.

Example 410C

A mixture of iron (1.5 g) and ammonium chloride (2.38 g) in water (40mL) was stirred at room temperature for 5 minutes. To this suspensionwas added EXAMPLE 410B in methanol (40 mL). The reaction mixture wasstirred at room temperature for 1 hour. Additional iron (1.8 g) wasadded to the reaction mixture, and it was stirred for another 3 hours.The solid from the reaction mixture was filtered off, and the filtratewas partitioned between water and ethyl acetate. The combined organiclayers were washed with brine, dried over MgSO₄, filtered, andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography on silica gel eluting with 1:4 ethylacetate\hexanes to give the title compound.

Example 410D 6-chloro-5-(trifluoromethyl)pyridine-3-sulfonyl chloride

Under ice-cooling, thionyl chloride (4 mL) was added dropwise over 20minutes to water (27 mL). The mixture was stirred overnight for 12 hoursto give a SO₂ containing solution. Separately, EXAMPLE 410C (1.14 g) indioxane (5 mL) was added to concentrated HCl (20 mL) at 0° C. Thesolution was stirred for 5 minutes. To this mixture was added sodiumnitrite (0.44 g) in water (6 mL) dropwise at 0° C. The solution stirredat 0° C. for three hours. During this time, any solids formed werecrushed with a glass rod to make sure that EXAMPLE 410C was completelyreacted. To the SO₂ containing solution was added copper(I) chloride(0.115 g). Then, to this solution was added the diazotized EXAMPLE 410Cat 0° C. The solution was stirred for 30 minutes. The reaction mixturewas extracted with ethyl acetate. The combined organic layers werewashed with brine, dried over MgSO₄, filtered, and concentrated underreduced pressure. The residue was purified by flash columnchromatography on silica gel eluting with 1:20 ethyl acetate\hexanes togive the title compound.

Example 410E 6-chloro-5-(trifluoromethyl)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 410D for5-bromo-6-chloropyridine-3-sulfonyl chloride in EXAMPLE 329A.

Example 410F

The title compound was prepared by substituting EXAMPLE 410E for EXAMPLE329A and EXAMPLE 306C for (tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE329B.

Example 410G4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 410F for EXAMPLE1F and EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 13.05 (s, 1H), 8.59 (s, 1H), 8.17 (d, 1H), 7.76(s, 1H), 7.62 (d, 1H), 7.37 (d, 2H), 7.00-7.08 (m, 4H), 6.78 (dd, 1H),6.51 (s, 1H), 6.11 (d, 1H), 4.56 (d, 2H), 3.77-3.80 (m, 2H), 3.57-3.62(m, 2H), 3.18 (br s, 2H), 2.32 (br s, 4H), 2.18 (br s, 2H), 1.99 (s,2H), 1.81-1.90 (m, 4H), 1.42 (t, 2H), 0.94 (s, 6H).

Example 4114-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 400E for EXAMPLE1E and EXAMPLE 432A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 13.09 (s, 1H), 8.57 (m, 1H), 8.37 (d, 1H), 7.81(s, 1H), 7.56 (dd, 1H), 7.52 (d, 1H), 7.38-7.31 (m, 3H), 7.11-7.07 (m,3H), 6.97 (d, 1H), 6.80 (dd, 1H), 6.52 (d, 1H), 6.17 (d, 1H), 3.84 (d,1H), 3.24-3.10 (m, 6H), 2.93 (d, 2H), 2.76 (m, 2H), 2.73 (s, 2H),2.34-2.10 (m, 8H), 1.97 (bs, 2H), 1.67 (m, 1H), 1.40 (t, 2H), 0.93 (s,6H), 0.47-0.26 (m, 4H).

Example 4124-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamideExample 412A tert-butyl (4,4-difluorocyclohexyl)methylcarbamate

Tert-butyl (4-oxocyclohexyl)methylcarbamate (5 g) and diethylaminosulfurtrifluoride (7.45 g) were stirred in dichloromethane (100 mL) for 24hours. The mixture was quenched with pH 7 buffer (100 mL), and pouredinto ether (400 mL). The resulting solution was separated, and theorganic layer was washed twice with water, and once with brine, and thenconcentrated to give the crude product and fluoroolefin in a 3:2 ratio.The crude product was taken up in tetrahydrofuran (70 mL) and water (30mL), and N-methylmorpholine-N-oxide (1.75 g), and OsO₄ (2.5 wt %solution in t-butanol) were added, and the mixture was stirred for 24hours. Na₂S₂O₃ (10 g) was then added, and the mixture was stirred for 30minutes. The mixture was then diluted with ether (300 mL), and theresulting solution was separated, and rinsed twice with water, and oncewith brine, and concentrated. The crude product was chromatographed onsilica gel using 5-10% ethyl acetate in hexanes to give the titlecompound.

Example 412B (4,4-difluorocyclohexyl)methanamine

A solution of EXAMPLE 412A (3 g) in dichloromethane (35 mL),trifluoroacetic acid (15 mL), and triethylsilane (1 mL) was stirred for2 hours. The solution was concentrated, then concentrated from toluene,and left on high vacuum for 24 hours. The semi-solid was taken up inether/hexane and filtered to give the product as its trifluoroaceticacid salt.

Example 412C4-((4,4-difluorocyclohexyl)methylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting EXAMPLE 412B for1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A.

Example 412D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 400E for EXAMPLE1E and EXAMPLE 412C for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 13.16 (s, 1H), 11.70 (br s, 1H), 8.65 (m, 1H),8.44 (d, 1H), 7.87 (d, 1H), 7.61 (dd, 2H), 7.41 (d, 2H), 7.02-7.20 (m,4H), 6.88 (dd, 1H), 6.58 (d, 1H), 6.26 (dd, 1H), 3.22 (m, 4H), 2.86 (m,2H), 2.20-2.35 (m, 7H), 2.14 (s, 2H), 2.10 (m, 2H), 2.03 (m, 2H), 1.91(m, 2H), 1.87 (m, 2H), 1.46 (m, 2H), 1.27-1.39 (m, 3H), 1.00 (s, 6H).

Example 413N-[(5-chloro-6-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamideExample 413A

The title compound was prepared by substituting EXAMPLE 387A for4-fluoro-3-nitrobenzenesulfonamide and EXAMPLE 409C for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 413BN-[(5-chloro-6-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 413A for EXAMPLE1F and EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 13.14 (s, 1H), 8.19 (d, 1H), 7.87 (s, 1H), 7.60(d, 1H), 7.56 (d, 1H), 7.36 (d, 2H), 7.31 (br s, 1H), 7.08-7.17 (m, 2H),7.06 (d, 2H), 6.80 (dd, 1H), 6.53 (d, 1H), 6.20 (d, 1H), 3.70-3.78 (m,4H), 3.43-3.54 (m, 2H), 3.18 (br s, 4H), 2.81 (s, 2H), 2.26 (br s, 4H),2.17 (br s, 2H), 1.97 (s, 2H), 1.64-1.80 (m, 4H), 1.40 (t, 2H), 0.94 (s,6H).

Example 414Trans-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamideExample 414A Cis-(4-methoxycyclohexyl)methanol andTrans-(4-methoxycyclohexyl)methanol

Ethyl 4-methoxycyclohexanecarboxylate (1 g) in tetrahydrofuran (10 mL)was treated with 1.0 N LiAlH₄ in THF (2 mL) at 0° C. The mixture wasstirred for 2 hours. The reaction was quenched with water (0.6 mL)followed by 2.0 N aqueous NaOH (0.2 mL). The mixture was stirred foranother 20 minutes, and the solid was filtered off. The filtrate wastaken up in ethyl acetate, washed with brine, dried over MgSO₄,filtered, and concentrated to give the title compound as a mixture ofcis and trans isomers.

Example 414B5-chloro-6-((trans-4-methoxycyclohexyl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 387A for EXAMPLE329A and EXAMPLE 414A for (tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE329B. The trans isomer was isolated by flash column chromatography onsilica gel.

Example 414CTrans-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 414B for EXAMPLE1F and EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 13.10 (s, 1H), 8.27 (d, 1H), 7.85 (d, 1H), 7.80(s, 1H), 7.59 (d, 1H), 7.36 (d, 2H), 7.03-7.10 (m, 4H), 6.79 (dd, 1H),6.53 (d, 1H), 6.14 (d, 1H), 4.19 (d, 2H), 3.24 (s, 3H), 3.20 (m, 4H),3.07-3.10 (m, 2H), 2.93 (br s, 2H), 2.39 (s, 4H), 2.18 (s, 2H),1.98-2.02 (m, 4H), 1.70-1.86 (m, 3H), 1.42 (t, 2H), 1.08-1.17 (m, 4H),0.94 (s, 6H).

Example 4152-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2,2-difluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamideExample 415A tert-Butyl2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxylate

This EXAMPLE was prepared by substituting tert-butyl2-(aminomethyl)morpholine-4-carboxylate for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 415B 4-(morpholin-2-ylmethylamino)-3-nitrobenzenesulfonamide

A solution of EXAMPLE 415A (0.8 g) in methylene chloride (10 mL) andtrifluoroacetic acid (10 mL) was stirred at room temperature for 2hours. The solvents were evaporated and the residue was triturated withdiethyl ether. The resulting solid was dissolved in 5% aqueous sodiumcarbonate solution (20 mL). The solution was evaporated to dryness andthe resulting solid was triturated with a solution of 10% methanol indichloromethane several times. Evaporation of the organic solution gavethe title compound.

Example 415C4-((4-(2,2-difluoroethyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

To a solution of EXAMPLE 415B (633 mg) in anhydrousN,N-dimethylformamide (10 mL) was added sodium carbonate (254 mg) and2,2-difluoroethyl iodide (422 mg). After stirring at 110° C. for 48hours, the mixture was concentrated. The residue was mixed with water(20 mL) and extracted with ethyl acetate. The crude product was purifiedon a silica gel column eluting with 10% methanol in methylene chlorideto give the title compound.

Example 415D2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2,2-difluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide

This EXAMPLE was prepared by substituting EXAMPLE 415C for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.26 (d, 1H), 8.87 (t,1H), 8.57 (s, 1H), 8.37 (dd, 1H), 7.99 (d, 1H), 7.53 (d, 1H), 7.43 (d,2H), 7.25 (m, 2H), 7.17 (d, 1H), 7.06 (d, 2H), 6.96 (d, 1H), 6.72-6.69(m, 2H), 6.31, 6.20, 6.09 (tt, 1H), 3.90 (m, 1H), 3.86 (d, 1H), 3.68(dt, 1H), 3.54-3.41 (m, 2H), 3.03 (m, 4H), 2.97 (d, 1H), 2.83-2.75 (m,4H), 2.69 (d, 1H), 2.35 (dt, 1H), 2.27-2.23 (m, 3H), 2.14 (m, 4H), 1.97(s, 2H), 1.38 (t, 2H), 0.94 (s, 6H).

Example 4164-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamideExample 416A5-bromo-3-fluoro-2-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine

The title compound was prepared by substituting EXAMPLE 306C for(tetrahydro-2H-pyran-4-yl)methanol and 5-bromo-2,3-difluoropyridine for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 279A.

Example 416B tert-butyl5-fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-ylcarbamate

EXAMPLE 416A (0.658 g), tert-butyl carbamate (0.300 g), palladium(II)acetate (0.024 g), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene(0.093 g) and cesium carbonate (1.044 g) were combined in a 20-mL vialwith dioxane (10.7 ml). The vial was flushed with nitrogen, capped andstirred at 100° C. overnight. The reaction mixture was diluted withethyl acetate, washed with water and brine, dried (MgSO₄), filtered,concentrated and chromatographed on silica gel with 20% ethyl acetate inhexanes as eluent.

Example 416C5-fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonylchloride

Under ice-cooling, thionyl chloride (1.563 mL) was added dropwise over20 minutes to water (9 mL). The mixture was stirred for 12 hours to givea SO₂-containing solution. Separately, EXAMPLE 416B (0.295 g) was addedto a mixture of dioxane (3.2 mL) and concentrated HCl (8 ml) at 0° C.The solution was stirred for 15 minutes, treated with a solution ofsodium nitrite (0.065 g) in water (2 mL) dropwise at 0° C. and stirredat 0° C. for three hours. The SO₂-containing solution was cooled to 0°C., treated sequentially with copper(I) chloride (0.042 g) and thediazotized mixture, and stirred for 30 minutes. The reaction mixture wasthen extracted with ethyl acetate and the organic layer was dried(MgSO₄), filtered and concentrated. The concentrate was chromatographedon silica gel with 5-10% ethyl acetate in hexanes as eluent.

Example 416D5-fluoro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridine-3-sulfonamide

EXAMPLE 416C (0.08 g) in isopropanol (2 mL) at 0° C. was treated withammonium hydroxide (1.70 mL) and stirred overnight. The reaction mixturewas concentrated to dryness, slurried in water, filtered, rinsed withwater and dried under vacuum to provide the title compound.

Example 416E4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 400E for EXAMPLE26C and EXAMPLE 416D for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (400 MHz,PYRIDINE-d₅) δ 14.67 (s, 1H), 8.84 (d, 1H), 8.38 (d, 1H), 8.06 (d, 1H),8.00 (dd, 1H), 7.46 (m, 2H), 7.35 (d, 1H), 7.12 (m, 3H), 6.87 (m, 2H),6.47 (d, 1H), 4.56 (d, 2H), 3.80 (m, 4H), 3.18 (m, 4H), 2.83 (s, 2H),2.31 (t, 2H), 2.24 (m, 4H), 1.99 (s, 2H), 1.86 (m, 4H), 1.41 (t, 2H),0.96 (s, 6H).

Example 4172-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamideExample 417A2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(3-nitro-4-(1-(tetrahydro-2H-pyran-4-yl)piperidin-4-ylamino)phenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 173C for EXAMPLE1F in EXAMPLE 403H.

Example 417B2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 417A for EXAMPLE403H in EXAMPLE 4031. ¹H NMR (500 MHz, pyridine-d₅) δ 9.27 (m, 1H), 8.59(s, 1H), 8.47 (d, 1H), 8.43 (d, 1H), 8.01 (d, 1H), 7.53 (d, 1H), 7.43(d, 2H), 7.24 (m, 1H), 7.18 (m, 1H), 7.07 (d, 2H), 6.96 (d, 1H), 6.70(m, 2H), 5.34 (m, 2H), 4.03 (m, 2H), 3.53 (m, 1H), 3.31 (m, 2H), 3.03(m, 4H), 2.82 (m, 2H), 2.76 (s, 2H), 2.42 (m, 1H), 2.32 (m, 2H),2.26-2.19 (m, 2H), 2.14 (m, 4H), 1.98 (m, 4H), 1.67-1.52 (m, 6H), 1.38(m, 2H), 0.94 (s, 6H).

Example 4182-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 418A2-(1-(bis(4-methoxyphenyl)methyl)-1H-benzo[d]imidazol-4-yloxy)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-(1-methylpiperidin-4-ylamino)-3-nitrophenylsulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 21A for EXAMPLE1F in EXAMPLE 403H.

Example 418B2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

The title compound was prepared by substituting EXAMPLE 418A for EXAMPLE403H in EXAMPLE 4031. ¹H NMR (500 MHz, pyridine-d₅) δ 9.25 (m, 1H), 8.58(s, 1H), 8.42 (m, 2H), 8.02 (d, 1H), 7.52 (d, 1H), 7.43 (d, 2H), 7.23(m, 1H), 7.14 (d, 1H), 7.07 (d, 2H), 6.92 (d, 1H), 6.70 (m, 2H), 5.52(m, 2H), 3.50 (m, 1H), 3.03 (m, 4H), 2.77 (s, 2H), 2.68 (m, 2H), 2.25(m, 2H), 2.20 (s, 3H), 2.14 (m, 6H), 1.97-1.90 (m, 4H), 1.67 (m, 2H),1.38 (t, 2H), 0.94 (s, 6H).

Example 419N-[(5-chloro-6-{[1-(cyanomethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamideExample 419A tert-butyl4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate

1-Tert-butyl 4-ethyl 4-fluoropiperidine-1,4-dicarboxylate (1.0 g) intetrahydrofuran (10 mL) at 0° C. was treated with a 1 N solution ofLiAlH₄ in tetrahydrofuran (2.54 mL), stirred for 2 hours at roomtemperature, treated sequentially dropwise with water (0.2 mL) and a 2 Naqueous solution of NaOH (0.6 mL), and stirred for 1 hour. The solid wasremoved by filtration through a pad of diatomaceous earth rinsing withethyl acetate. The filtrate was washed with water and brine, dried(MgSO₄), filtered and concentrated to give the title compound.

Example 419B tert-butyl4-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)-4-fluoropiperidine-1-carboxylate

The title compound was prepared by substituting EXAMPLE 419A for(tetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 387A for4-fluoro-3-nitrobenzenesulfonamide in EXAMPLE 279A.

Example 419C5-chloro-6-((4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide,2*trifluoroacetic acid salt

The title compound was prepared by substituting EXAMPLE 419B for EXAMPLE1A in EXAMPLE 1B.

Example 419D5-chloro-6-((1-(cyanomethyl)-4-fluoropiperidin-4-yl)methoxy)pyridine-3-sulfonamide

EXAMPLE 419C (0.166 g) in acetonitrile (3.00 mL) was treated with2-chloroacetonitrile (0.027 g) and sodium carbonate (0.064 g), heated at60° C. overnight, cooled to room temperature and chromatographed onsilica gel with 0 to 3% methanol in CH₂Cl₂ as eluent. The obtained solidwas slurried in water, filtered, rinsed with water and diethyl ether,and dried in a vacuum oven at 80° C. to provide the title compound

Example 419EN-[(5-chloro-6-{[1-(cyanomethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 400E for EXAMPLE26C and EXAMPLE 419D for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (400 MHz,PYRIDINE-d₅) δ 14.70 (s, 1H), 8.91 (d, 1H), 8.39 (d, 2H), 8.10 (d, 1H),7.46 (m, 2H), 7.35 (d, 1H), 7.11 (m, 3H), 6.87 (m, 2H), 6.50 (d, 1H),4.49 (d, 2H), 3.72 (s, 2H), 3.17 (m, 4H), 2.82 (s, 2H), 2.72 (m, 4H),2.31 (m, 2H), 2.23 (m, 4H), 2.06 (m, 2H), 1.99 (s, 2H), 1.89 (m, 2H),1.41 (t, 2H), 0.96 (s, 6H).

Example 4204-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydrofuran-3-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamideExample 420A5-chloro-6-((tetrahydrofuran-3-yl)methoxy)pyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 387A for EXAMPLE329A and (tetrahydrofuran-3-yl)methanol for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 329B.

Example 420B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydrofuran-3-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 420B for EXAMPLE1F and EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 13.07 (s, 1H), 8.25 (d, 1H), 7.85 (d, 1H), 7.79(s, 1H), 7.60 (d, 1H), 7.36 (d, 2H), 7.03-7.09 (m, 4H), 6.78 (dd, 1H),6.51 (d, 1H), 6.13 (dd, 1H), 4.25-4.37 (m, 2H), 3.77-3.81 (m, 2H),3.64-3.70 (m, 2H), 3.54-3.57 (m, 2H), 3.17 (br s, 4H), 2.89 (br s, 2H),2.68-2.71 (m, 1H), 2.33 (m, 3H), 2.16-2.18 (m, 2H), 1.98-2.01 (m, 3H),1.66-1.71 (m, 1H), 1.41 (t, 2H), 0.94 (s, 6H).

Example 421Trans-N-({5-chloro-6-[(4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamideExample 421A6-((trans-4-(tert-butyldimethylsilyloxy)cyclohexyl)methoxy)-5-chloropyridine-3-sulfonamide

The title compound was prepared by substituting EXAMPLE 387A for EXAMPLE329A and trans-4-(tert-butyldimethylsilyloxy)cyclohexylmethanol,synthesized according to the procedure reported in WO 2008/124878 (Page100), for (tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 329B.

Example 421B

Trans-N-({5-chloro-6-[(4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 421A for EXAMPLE1F and EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177, after removal of thetert-butyldimethylsilyl group with trifluoroacetic acid. ¹H NMR (500MHz, dimethylsulfoxide-d₆) δ 13.12 (s, 1H), 8.29 (d, 1H), 7.88 (d, 1H),7.84 (s, 1H), 7.40 (d, 2H), 7.07-7.13 (m, 4H), 6.83 (dd, 1H), 6.56 (s,1H), 6.17 (d, 1H), 4.58 (d, 1H), 4.21 (d, 2H), 3.22 (br s, 4H),2.36-2.40 (m, 3H), 2.20-2.24 (m, 2H), 2.02-2.03 (m, 2H), 1.75-1.89 (m,5H), 1.45 (t, 2H), 1.11-1.21 (m, 4H), 0.98 (s, 6H).

Example 422N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamideExample 422A (R)-tert-butyl3-(3-chloro-5-sulfamoylpyridin-2-yloxy)pyrrolidine-1-carboxylate

The title compound was prepared by substituting (R)-tert-butyl3-hydroxypyrrolidine-1-carboxylate for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 387B.

Example 422B (R)-5-chloro-6-(pyrrolidin-3-yloxy)pyridine-3-sulfonamideHydrochloride salt

EXAMPLE 422A (480 mg) was dissolved in anhydrous tetrahydrofuran (10 mL)followed by addition of hydrogen chloride in dioxane solution (4M, 2.5mL). The reaction mixture was stirred at room temperature overnight. Thesolvent was removed under vacuum to provide the title compound.

Example 422C(R)-5-chloro-6-(1-(2,2-difluoroethyl)pyrrolidin-3-yloxy)pyridine-3-sulfonamide

A reaction mixture of EXAMPLE 422B (353 mg), 1,1-difluoro-2-iodoethane(268 mg) and Na₂CO₃ (283 mg) in N,N-dimethylformamide (10 mL) was heatedat 80° C. overnight. The reaction mixture was cooled to room temperatureand diluted with ethyl acetate. The organic phase was washed with waterand brine, dried over anhydrous sodium sulfate, and concentrated. Thecrude material was purified with 2.5-3% methanol/dichloromethane toafford the title compound.

Example 422DN-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 400E for EXAMPLE26C and EXAMPLE 422C for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 12.98 (s, 1H), 8.17 (d, 1H), 7.80 (d, 1H), 7.73(s, 1H), 7.66 (d, 1H), 7.35 (d, 2H), 7.05 (m, 4H), 6.73 (m, 1H), 6.41(d, 1H), 6.10 (m, 2H), 5.37 (m, 1H), 2.92 (m, 11H), 2.56 (m, 2H), 2.24(m, 7H), 1.99 (m, 2H), 1.82 (m, 1H), 1.39 (m, 2H), 0.93 (s, 6H).

Example 4232-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamideExample 423A (S)-tert-Butyl2-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)morpholine-4-carboxylate

This EXAMPLE was prepared by substituting (S)-tert-butyl2-(hydroxymethyl)morpholine-4-carboxylate for4-hydroxymethyl-tetrahydropyran in EXAMPLE 387B.

Example 423B(S)-5-chloro-6-(morpholin-2-ylmethoxy)pyridine-3-sulfonamide

This EXAMPLE was prepared by substituting EXAMPLE 423A for EXAMPLE 415Ain EXAMPLE 415B.

Example 423C

(S)-5-chloro-6-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methoxy)pyridine-3-sulfonamide

To a solution of EXAMPLE 423B (0.32 g) in anhydrousN,N-dimethylformamide (10 mL) was added sodium carbonate (0.165 g) and2-(dimethylamino)acetyl chloride hydrochloride (0.40 g). After stirredat ambient temperature overnight, the mixture was concentrated todryness. The residue was mixed with 5% aqueous Na₂CO₃ (20 mL) andextracted with ethyl acetate. The crude product was purified on a silicagel column eluting with 10% methanol in dichloromethane saturated withammonia to give the title compound.

Example 423D2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 423C for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.08 (d, 1H), 8.60 (t,1H), 8.57 (s, 1H), 8.01 (d, 1H), 7.53 (d, 1H), 7.43 (d, 2H), 7.25 (m,2H), 7.15 (m, 1H), 7.07 (d, 2H), 6.73-6.69 (m, 2H), 4.86-4.36 (m, 4H),4.05-3.90 (m, 1H), 3.88 (d, 1H), 3.62-3.18 (m, 4H), 3.04 (m, 4H), 2.87(t, 1H), 2.77 (s, 2H), 2.33 (m, 6H), 2.26 (m, 2H), 2.15 (m, 4H), 1.97(s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 4242-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamideExample 424A (R)-tert-butyl2-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)morpholine-4-carboxylate

This EXAMPLE was prepared by substituting (R)-tert-butyl2-(hydroxymethyl)morpholine-4-carboxylate for4-hydroxymethyl-tetrahydropyran in EXAMPLE 387B.

Example 424B(R)-5-chloro-6-(morpholin-2-ylmethoxy)pyridine-3-sulfonamide

This EXAMPLE was prepared by substituting EXAMPLE 424A for EXAMPLE 415Ain EXAMPLE 415B.

Example 424C(R)-5-chloro-6-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methoxy)pyridine-3-sulfonamide

This EXAMPLE was prepared by substituting EXAMPLE 424B for EXAMPLE 423Bin EXAMPLE 423C.

Example 424D2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 424C for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.08 (d, 1H), 8.60 (t,1H), 8.57 (s, 1H), 8.01 (d, 1H), 7.53 (d, 1H), 7.43 (d, 2H), 7.25 (m,2H), 7.15 (m, 1H), 7.07 (d, 2H), 6.73-6.69 (m, 2H), 4.86-4.36 (m, 4H),4.05-3.90 (m, 1H), 3.88 (d, 1H), 3.62-3.18 (m, 4H), 3.04 (m, 4H), 2.87(t, 1H), 2.77 (s, 2H), 2.33 (m, 6H), 2.26 (m, 2H), 2.15 (m, 4H), 1.97(s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 425N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 400E for EXAMPLE 1Eand EXAMPLE 423C for EXAMPLE 1F in EXAMPLE 1G, and was purified byreverse-phase HPLC using a Waters Preparative LC4000 system withPhenomenex Luna C18 column and a water-acetonitrile mobile phasebuffered with ammonium acetate. ¹H NMR (500 MHz, pyridine-d₅) δ 8.87(dd, 1H), 8.40 (t, 2H), 8.13 (dd, 1H), 7.46 (d, 2H), 7.35 (d, 1H),7.15-7.10 (m, 3H), 6.87 (d, 1H), 6.85 (s, 1H), 6.50 (dd, 1H), 4.84-4.46(m, 4H), 4.02-3.90 (m, 1H), 3.88 (m, 1H), 3.60-3.33 (m, 2H), 3.25-3.15(m, 6H), 2.89-2.84 (m, 1H), 2.83 (s, 2H), 2.32-2.23 (m, 12H), 1.99 (s,2H), 1.41 (t, 2H), 0.96 (s, 6H).

1250969 EXAMPLE 426 Gary WangN-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 400E for EXAMPLE 1Eand EXAMPLE 424C for EXAMPLE 1F in EXAMPLE 1G, and was purified byreverse-phase HPLC using a Waters Preparative LC4000 system withPhenomenex Luna C18 column and a water-acetonitrile mobile phasebuffered with ammonium acetate. ¹H NMR (500 MHz, pyridine-d₅) δ 8.87(dd, 1H), 8.40 (t, 2H), 8.13 (dd, 1H), 7.46 (d, 2H), 7.35 (d, 1H),7.15-7.10 (m, 3H), 6.87 (d, 1H), 6.85 (s, 1H), 6.50 (dd, 1H), 4.84-4.46(m, 4H), 4.02-3.90 (m, 1H), 3.88 (m, 1H), 3.60-3.33 (m, 2H), 3.25-3.15(m, 6H), 2.89-2.84 (m, 1H), 2.83 (s, 2H), 2.32-2.23 (m, 12H), 1.99 (s,2H), 1.41 (t, 2H), 0.96 (s, 6H).

Example 4274-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 387B for EXAMPLE1F and EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 13.09 (s, 1H), 8.27 (d, 1H), 7.85 (d, 1H), 7.80(s, 1H), 7.59 (d, 1H), 7.36 (d, 2H), 7.03-7.10 (m, 4H), 6.79 (dd, 1H),6.52 (d, 1H), 6.13 (d, 1H), 4.27 (d, 2H), 3.88 (dd, 2H), 3.19 (br s,4H), 2.91 (br s, 2H), 2.36-2.40 (br, 3H), 2.18 (m, 2H), 2.05 (m, 1H),1.98 (s, 2H), 1.64-1.68 (m, 2H), 1.34-1.43 (m, 4H), 1.11-1.21 (m, 4H),0.94 (s, 6H).

Example 4282-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(cyanomethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamideExample 428A8-{4-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enylmethyl]piperazin-1-yl}-6-oxa-2,11a-diazadibenzo[c,d,g]azulen-11-one

A solution of EXAMPLE 403G (4.5 g) in anhydrous dichloromethane (100 mL)was cooled in an ice bath and catalytic N,N-dimethylformamide was added.This was followed by the dropwise addition of a solution of oxalyldichloride (1.231 mL) in anhydrous methylene chloride (5 mL). The icebath was removed and the reaction stirred for 1 hour while warming toambient temperature. The reaction was quenched by the addition of ice(150 mL) and saturated sodium bicarbonate solution (100 mL). The mixturewas further diluted with saturated sodium bicarbonate solution (200 mL)and methylene chloride (200 mL). The organic layer was purified onsilica gel, and was eluted with a 0, 10, 25, and 100% ethyl acetate inmethylene chloride step gradient to provide the title compound.

Example 428B (R)-tert-butyl3-(2-nitro-4-sulfamoylphenylamino)pyrrolidine-1-carboxylate

To a solution of (R)-tert-butyl 3-aminopyrrolidine-1-carboxylate (1.0g), tetrahydrofuran (50 ml), N-ethyl-N-isopropylpropan-2-amine (5.61 mL)and N,N-dimethylformamide (10 mL) was added4-fluoro-3-nitrobenzenesulfonamide (1.212 g) and the mixture was stirredfor 18 hours. The crude product was isolated by concentration and wasthe material was purified on silica gel, and was eluted with a 30, 50,and 75% ethyl acetate in hexane step gradient to provide the titlecompound.

Example 428C (R)-3-nitro-4-(pyrrolidin-3-ylamino)benzenesulfonamide

A suspension of EXAMPLE 428B (2.018 g) in anhydrous dichloromethane (25mL) was cooled in an ice bath and 2,2,2-trifluoroacetic acid (20 mL) wasadded. After stirring 15 minutes, the ice bath was removed and thereaction was allowed to come to ambient temperature over 2 hours. Thereaction mixture was concentrated and the residue was dissolved in waterand basified with aqueous sodium carbonate solution. The mixture wasextracted repeatedly with 10% methanol in methylene chloride and theorganics were concentrated to provide the title compound.

Example 428D(R)-4-(1-(cyanomethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide

To a solution of EXAMPLE 428C (440 mg) in anhydrousN,N-dimethylformamide (10 mL) was added sodium carbonate (132 mg). Tothe resulting suspension was added 2-bromoacetonitrile (0.077 mL) andthe mixture was heated at 60° C. for 18 hours. The crude material wasisolated by concentration and was purified on silica gel, and was elutedwith a 0.5, 2.5, and 5% methanol in methylene chloride step gradient toprovide the title compound.

Example 428E2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(cyanomethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

To a solution of EXAMPLE 428D (82.6 mg) in tetrahydrofuran (7 mL) wasadded 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.063 mL). Thismixture was stirred at ambient temperature for 45 minutes and a solutionof EXAMPLE 428A (117 mg) in tetrahydrofuran (3 mL) was added. Afterstirring 18 hours, the crude product was isolated by concentration andwas purified by reverse phase chromatography with ammonium acetatebuffer in acetonitrile to give the title compound. ¹H NMR (400 MHz,pyridine-d₅) δ 9.27 (d, 1H), 8.59 (s, 1H), 8.55 (d, 1H), 8.40 (dd, 1H),7.99 (d, 1H), 7.54 (m, 1H), 7.43 (d, 2H), 7.25 (m, 1H), 7.16 (m, 1H),7.07 (d, 2H), 6.86 (d, 1H), 6.69 (m, 2H), 5.73 (m, 2H), 4.15 (m, 1H),3.90 (s, 2H), 3.03 (m, 4H), 2.96-287. (m, 2H), 2.81-2.76 (m, 3H), 2.58(m, 1H), 2.32-2.23 (m, 3H), 2.14 (m, 4H), 1.97 (s, 2H), 1.73 (m, 1H),1.38 (t, 2H), 0.94 (s, 6H).

Example 4292-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-(2-methoxyethoxy)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}benzamideExample 429A(R)-4-(1-(2-(2-methoxyethoxy)ethyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting1-bromo-2-(2-methoxyethoxy)ethane for 2-bromoacetonitrile in EXAMPLE428D.

Example 429B2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-(2-methoxyethoxy)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}benzamide

The title compound was prepared by substituting EXAMPLE 429A for EXAMPLE428D in EXAMPLE 428E. ¹H NMR (400 MHz, pyridine-d₅) δ 9.26 (d, 1H), 8.58(m, 2H), 8.38 (dd, 1H), 8.01 (d, 1H), 7.53 (d, 1H), 7.43 (d, 2H), 7.25(d, 1H), 7.16 (d, 1H), 7.07 (d, 2H), 6.85 (d, 1H), 6.71-6.69 (m, 2H),5.33 (m, 2H), 4.05 (m, 1H), 3.63 (m, 4H), 3.54 (m, 2H), 3.29 (s, 3H),3.03 (m, 4H), 2.86 (m, 1H), 2.77 (m, 4H), 2.70 (t, 2H), 2.38 (m, 1H),2.27-2.18 (m, 3H), 2.14 (m, 4H), 1.97 (s, 2H), 1.64 (m, 1H), 1.38 (t,2H), 0.94 (s, 6H).

Example 4302-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(N,N-dimethylglycyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamideExample 430AR)-4-(1-(2-(dimethylamino)acetyl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide

The title compound was prepared by substituting 2-(dimethylamino)acetylchloride for 2-bromoacetonitrile in EXAMPLE 428D.

Example 430B2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(N,N-dimethylglycyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

The title compound was prepared by substituting EXAMPLE 430A for EXAMPLE428D in EXAMPLE 428E. ¹H NMR (400 MHz, pyridine-d₅) δ 9.25 (m, 1H), 8.59(d, 1H), 8.47-8.35 (m, 2H), 8.01 (d, 1H), 7.54 (d, 1H), 7.44 (d, 2H),7.25-7.20 (m, 2H), 7.16-6.92 (m, 4H), 6.71 (m, 2H), 5.55 (m, 1H),4.34-4.18 (m, 1H), 4.03 (m, 1H), 3.84-3.63 (m, 3H), 3.44-3.34 (m, 2H),3.03 (m, 4H), 2.77 (s, 2H), 2.43 (m, 6H), 2.25 (m, 3H), 2.14 (m, 4H),2.03-1.83 (m, 3H), 1.38 (t, 2H), 0.94 (s, 6H).

Example 4312-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(cyanomethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamideExample 431A4-((4-(cyanomethyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

This EXAMPLE was prepared by substituting 2-bromo-acetonitrile for2,2-difluoroethyl iodide in EXAMPLE 415C at ambient temperature.

Example 431B2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(cyanomethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide

This EXAMPLE was prepared by substituting EXAMPLE 431A for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.25 (d, 1H), 8.87 (t,1H), 8.58 (s, 1H), 8.38 (dd, 1H), 8.00 (d, 1H), 7.53 (d, 1H), 7.43 (d,2H), 7.25 (m, 2H), 7.16 (d, 1H), 7.07 (d, 2H), 6.97 (d, 1H), 6.73-6.68(m, 2H), 3.96-3.85 (m, 2H), 3.78 (s, 2H), 3.66 (dt, 1H), 3.53-3.42 (m,2H), 3.03 (m, 4H), 2.90 (d, 1H), 2.76 (s, 2H), 2.61 (d, 1H), 2.51 (dt,1H), 2.40 (t, 1H), 2.25 (m, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.38 (t,2H), 0.94 (s, 6H).

Example 4322-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamideExample 432A4-((4-cyclopropylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

A solution of EXAMPLE 415B (0.633 g) and(1-ethoxycyclopropoxy)trimethylsilane (1.601 ml) in anhydrous methanol(15 mL) and acetic acid (1.7 ml) was refluxed for 30 minutes and allowedto cool to room temperature. Sodium cyanoborohydride (0.377 g) was thenadded and the mixture was stirred at ambient temperature overnight. Thereaction mixture was concentrated to dryness. The residue was mixed with5% aqueous Na₂CO₃ solution (25 mL) and extracted with ethyl acetate. Thecrude product was purified on a silica gel column eluting with 5% and10% methanol in dichloromethane to provide the title compound.

Example 432B2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

This EXAMPLE was prepared by substituting EXAMPLE 432A for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.25 (d, 1H), 8.89 (t,1H), 8.57 (s, 1H), 8.38 (dd, 1H), 8.00 (d, 1H), 7.53 (d, 1H), 7.43 (d,2H), 7.25 (m, 2H), 7.16 (d, 1H), 7.07 (d, 2H), 6.98 (d, 1H), 6.73-6.68(m, 2H), 3.90-3.83 (m, 2H), 3.60 (dt, 1H), 3.55-3.41 (m, 2H), 3.03 (m,4H), 2.96 (d, 1H), 2.76 (s, 2H), 2.69 (d, 1H), 2.35 (dt, 1H), 2.26-2.20(m, 3H), 2.14 (m, 4H), 1.97 (s, 2H), 1.59 (m, 1H), 1.38 (t, 2H), 0.94(s, 6H), 0.47-0.37 (m, 4H).

Example 4332-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-oxetan-3-ylmorpholin-2-yl)methyl]amino}phenyl)sulfonyl]benzamideExample 433A3-nitro-4-((4-(oxetan-3-yl)morpholin-2-yl)methylamino)benzenesulfonamide

This EXAMPLE was prepared by substituting oxetan-3-one for(1-ethoxycyclopropoxy)-trimethylsilane in EXAMPLE 432A.

Example 433B2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-oxetan-3-ylmorpholin-2-yl)methyl]amino}phenyl)sulfonyl]benzamide

This EXAMPLE was prepared by substituting EXAMPLE 433A for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.25 (d, 1H), 8.87 (t,1H), 8.57 (s, 1H), 8.38 (dd, 1H), 8.02 (d, 1H), 7.53 (d, 1H), 7.44 (d,2H), 7.24 (m, 2H), 7.13 (d, 1H), 7.07 (d, 2H), 6.98 (d, 1H), 6.73-6.68(m, 2H), 4.69-4.62 (m, 4H), 3.98-3.88 (m, 2H), 3.69 (dt, 1H), 3.55-3.35(m, 3H), 3.03 (m, 4H), 2.77 (s, 2H), 2.74 (d, 1H), 2.44 (d, 1H), 2.25(m, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.94 (m, 1H), 1.87 (t, 1H), 1.38(t, 2H), 0.94 (s, 6H).

Example 434N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}oxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamideExample 434A(R)-5-chloro-6-(1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yloxy)pyridine-3-sulfonamide

EXAMPLE 422B (278 mg) and 1,3-difluoropropan-2-one (94 mg) weresuspended in dichloroethane (10 ml). N,N-dimethylformamide (1.5 mL) wasadded drop wise until a white milky suspension formed. The reactionmixture was stirred at room temperature for 15 minutes followed by theaddition of sodium triacetoxyborohydride (424 mg). The reaction mixturewas stirred at room temperature overnight. The solvent was removed undervacuum, and the crude material was purified with 2.5-5%methanol/dichloromethane to afford the title compound.

Example 434BN-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}oxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide

The title compound was prepared by substituting EXAMPLE 400E for EXAMPLE26C and EXAMPLE 434A for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 12.96 (s, 1H), 8.16 (d, 1H), 7.79 (m, 1H), 7.69(m, 2H), 7.35 (d, 2H), 7.05 (m, 4H), 6.72 (m, 1H), 6.39 (d, 1H), 6.09(dd, 3.05 Hz, 1H), 5.37 (m, 1H), 4.66 (t, 2H), 4.54 (t, 2H), 2.91 (m,12H), 2.23 (m, 7H), 1.97 (s, 2H), 1.82 (m, 1H), 1.40 (t, 2H), 0.93 (s,6H).

Example 4354-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamideExample 435A (R)-1-(1,3-difluoropropan-2-yl)pyrrolidin-3-amine

To a solution of (R)-tert-butyl pyrrolidin-3-ylcarbamate (0.500 g) and1,3-difluoropropan-2-one (0.278 g) in dichloromethane (5 mL) was addedsodium triacetoxyborohydride (0.853 g). After stirring for one hour, thereaction was quenched with saturated aqueous NaHCO₃ solution (5 mL). Themixture was extracted with dichloromethane (25 mL), and the organiclayer was dried over anhydrous magnesium sulfate, filtered, andconcentrated. The resulting residue was treated with HCl (4.0M in1,4-dioxane, 4 mL) and methanol (1 mL) and stirred for one hour. Themixture was concentrated to give the title compound.

Example 435B(R)-4-(1-(1,3-difluoropropan-2-yl)pyrrolidin-3-ylamino)-3-nitrobenzenesulfonamide

To 4-fluoro-3-nitrobenzenesulfonamide (0.272 g) and EXAMPLE 435A (0.195g) in tetrahydrofuran (3.0 mL) was addedN-ethyl-N-isopropylpropan-2-amine (0.512 mL) and the reaction stirred atroom temperature. After stirring for six hours, the reaction wasconcentrated, loaded onto silica gel (Reveleris 40 g) and the producteluted using a gradient of 25-100% ethyl acetate/hexanes over 30 minutesto give the title compound.

Example 435C4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-4-yloxy]-benzoicacid methyl ester

EXAMPLE 400D (1000 mg) was dissolved in N,N-dimethylformamide (12 mL)and sodium hydride (60% in mineral oil, 45 mg) was added. The solutionwas stirred at room temperature for 15 minutes,2-(trimethylsilyl)ethoxymethyl chloride (299 mg) was added, and thesolution was stirred at room temperature for 45 minutes. The solutionwas added to water and extracted with ethyl acetate. The extract waswashed with brine, dried on anhydrous sodium sulfate, filtered,concentrated and purified by flash column chromatography on silica gelusing 30-50% ethyl acetate in hexanes.

Example 435D4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-4-yloxy]-benzoicacid

This example was prepared by substituting EXAMPLE 435C for EXAMPLE 1D inEXAMPLE 1E.

Example 435EN-{4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-4-yloxy]-benzoyl}-4-[(R)-1-(2-fluoro-1-fluoromethyl-ethyl)-pyrrolidin-3-ylamino]-3-nitro-benzenesulfonamide

This example was prepared by substituting EXAMPLE 435D for EXAMPLE 1Eand EXAMPLE 435B for EXAMPLE 1F in EXAMPLE 1G.

Example 435F4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide

EXAMPLE 435E (103 mg) was dissolved in trifluoroacetic acid (1.8 mL) andwater (0.2 mL) and stirred at room temperature for 90 minutes. Thesolvents were removed under vacuum, the residue dissolved in 1,4-dioxane(2 mL) and treated with 1M sodium hydroxide (1 mL), and the solutionstirred at room temperature for 30 minutes. The solution was added to asaturated aqueous sodium bicarbonate solution and extracted withdichloromethane. The extract was washed with brine, dried on anhydroussodium sulfate, filtered, and the solvent removed under vacuum. ¹H NMR(300 MHz, dimethylsulfoxide-d₆) δ 13.09 (bs, 1H), 8.37 (m, 2H), 7.84 (d,1H), 7.58-7.45 (m, 2H), 7.36 (d, 2H), 7.17-7.03 (m, 4H), 6.95 (dd, 1H),6.84-6.76 (m, 1H), 6.53 (dd, 1H), 6.17 (t, 1H), 4.72 (d, 2H), 4.56 (d,2H), 4.23 (m, 1H), 3.17 (m, 4H), 3.12-3.03 (m, 2H), 3.02-2.91 (m, 2H),2.86-2.73 (m, 4H), 2.40-2.14 (m, 6H), 1.97 (bs, 2H), 1.70 (m, 1H), 1.40(t, 2H), 0.94 (s, 6H).

Example 4364-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamideExample 436A4-(1-cyclopropyl-piperidin-4-ylamino)-3-nitro-benzenesulfonamide

This example was prepared by substituting1-cyclopropyl-piperidin-4-ylamine for1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A.

Example 436BN-{4-{4-[2-(4-chlorophenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-4-yloxy]-benzoyl}-4-(1-cyclopropyl-piperidin-4-ylamino)-3-nitro-benzenesulfonamide

This example was prepared by substituting EXAMPLE 435D for EXAMPLE 1Eand EXAMPLE 436A for EXAMPLE 1F in EXAMPLE 1G.

Example 436C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 436B for EXAMPLE 435Ein EXAMPLE 435F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 13.05 (bs,1H), 8.35 (d, 1H), 8.17 (d, 1H), 7.77 (bs, 1H), 7.57 (td, 2H), 7.35 (d,2H), 7.09-7.03 (m, 4H), 6.98 (d, 1H), 6.77 (dd, 1H), 6.48 (bs, 1H), 6.17(m, 1H), 3.66 (m, 1H), 3.12 (bs, 4H), 2.92 (m, 2H), 2.76 (bs, 2H), 2.21(m, 8H), 1.97 (bs, 2H), 1.94 (m, 2H), 1.73 (m, 1H), 1.55 (m, 2H), 1.40(t, 2H), 0.93 (s, 6H), 0.46 (d, 2H), 0.35 (bs, 2H).

Example 4372-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamideExample 437A (R)-tert-butyl2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxylate

This example was prepared by substituting (R)-tert-butyl2-(aminomethyl)morpholine-4-carboxylate for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 437B (S)-4-(morpholin-2-ylmethylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting EXAMPLE 437A for EXAMPLE 415Ain EXAMPLE 415B.

Example 437C(R)-4-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting EXAMPLE 437B for EXAMPLE 423Bin EXAMPLE 423C.

Example 437D2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 437C for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.25 (s, 1H), 8.86 (t,1H), 8.57 (s, 1H), 8.38 (t, 1H), 8.02 (d, 1H), 7.53 (d, 1H), 7.44 (d,2H), 7.24 (m, 2H), 7.13 (d, 1H), 7.07 (d, 2H), 6.97 (dd, 1H), 6.73-6.68(m, 2H), 4.75, 4.50 (dd, 1H), 4.33, 4.02 (dd, 1H), 3.93 (m, 1H),3.85-3.70 (m, 1H), 3.65-3.40 (m, 3H), 3.33 (dd, 1H), 3.25-3.10 (m, 2H),3.03 (m, 4H), 2.90 (m, 1H), 2.77 (s, 2H), 2.27-2.25 (m, 8H), 2.14 (m,4H), 1.97 (s, 2H), 1.38 (t, 2H), 0.94 (s, 6H).

Example 4382-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamideExample 438A (S)-tert-butyl2-((2-nitro-4-sulfamoylphenylamino)methyl)morpholine-4-carboxylate

This example was prepared by substituting (S)-tert-butyl2-(aminomethyl)morpholine-4-carboxylate for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 438B (R)-4-(morpholin-2-ylmethylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting EXAMPLE 438A for EXAMPLE 415Ain EXAMPLE 415B.

Example 438C(S)-4-((4-(2-(dimethylamino)acetyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting EXAMPLE 438B for EXAMPLE 423Bin EXAMPLE 423C.

Example 438D2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 438C for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.25 (s, 1H), 8.86 (t,1H), 8.57 (s, 1H), 8.38 (t, 1H), 8.02 (d, 1H), 7.53 (d, 1H), 7.44 (d,2H), 7.24 (m, 2H), 7.13 (d, 1H), 7.07 (d, 2H), 6.97 (dd, 1H), 6.73-6.68(m, 2H), 4.75, 4.50 (dd, 1H), 4.33, 4.02 (dd, 1H), 3.93 (m, 1H),3.85-3.70 (m, 1H), 3.65-3.40 (m, 3H), 3.33 (dd, 1H), 3.25-3.10 (m, 2H),3.03 (m, 4H), 2.90 (m, 1H), 2.77 (s, 2H), 2.27-2.25 (m, 8H), 2.14 (m,4H), 1.97 (s, 2H), 1.38 (t, 2H), 0.94 (s, 6H).

Example 4392-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)benzamideExample 439A3-nitro-4-((tetrahydrofuran-3-yl)methylamino)benzenesulfonamide

This example was prepared by substituting(tetrahydrofuran-3-yl)methylamine for (tetrahydropyran-4-yl)methylaminein EXAMPLE 1F.

Example 439B2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 439A for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.26 (d, 1H), 8.70 (t,1H), 8.57 (s, 1H), 8.40 (dd, 1H), 8.01 (d, 1H), 7.51 (d, 1H), 7.44 (d,2H), 7.24 (m, 2H), 7.14 (d, 1H), 7.07 (d, 2H), 6.89 (d, 1H), 6.73-6.68(m, 2H), 3.93-3.89 (m, 1H), 3.83 (dd, 1H), 3.83-3.68 (m, 2H), 3.33-3.23(m, 2H), 3.03 (m, 4H), 2.77 (s, 2H), 2.55-2.50 (m, 1H), 2.25 (m, 2H),2.14 (m, 4H), 2.00-1.93 (m, 3H), 1.65-1.58 (m, 1H), 1.38 (t, 2H), 0.94(s, 6H).

Example 440Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 311B for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.29 (d, 1H), 8.67 (t,1H), 8.59 (s, 1H), 8.41 (dd, 1H), 7.99 (d, 1H), 7.52 (d, 1H), 7.43 (d,2H), 7.24 (m, 1H), 7.17 (m, 1H), 7.07 (d, 2H), 6.90 (d, 1H), 6.72-6.68(m, 2H), 5.97 (m, 2H), 3.29 (s, 3H), 3.14 (t, 2H), 3.02 (m, 5H), 2.76(s, 2H), 2.25 (m, 2H), 2.13 (m, 4H), 2.07 (m, 2H), 1.97 (s, 2H), 1.82(m, 2H), 1.57 (m, 1H), 1.38 (t, 2H), 1.22 (m, 2H), 1.01 (m, 2H), 0.94(s, 6H).

Example 4412-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 409D for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.27 (d, 1H), 8.84 (t,1H), 8.57 (s, 1H), 8.41 (dd, 1H), 7.99 (d, 1H), 7.52 (d, 1H), 7.43 (d,2H), 7.23 (m, 1H), 7.15 (m, 1H), 7.14-7.02 (m, 3H), 6.70 (m, 2H), 6.49(m, 2H), 3.86 (m, 2H), 3.76-3.69 (m, 3H), 3.65 (d, 1H), 3.03 (m, 4H),2.76 (s, 2H), 2.25 (m, 2H), 2.14 (m, 4H), 1.97 (s, 2H), 1.92-1.76 (m,4H), 1.38 (t, 2H), 0.94 (s, 6H).

Example 4422-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 416D for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.02 (d, 1H), 8.59 (s,1H), 8.35 (m, 1H), 8.01 (d, 1H), 7.51 (d, 1H), 7.44 (d, 2H), 7.22 (m,2H), 7.12 (d, 1H), 7.07 (d, 2H), 6.84 (m, 1H), 6.73 (m, 2H), 4.59 (s,1H), 4.54 (s, 1H), 3.89-3.74 (m, 4H), 3.05 (m, 4H), 2.78 (s, 2H), 2.26(m, 2H), 2.16 (m, 4H), 2.02-1.81 (m, 6H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 4432-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide

This example was prepared by substituting EXAMPLE 404A for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.12 (d, 1H), 8.68 (d,1H), 8.59 (s, 1H), 7.99 (d, 1H), 7.52 (d, 1H), 7.44 (d, 2H), 7.24 (d,1H), 7.15 (d, 1H), 7.07 (d, 2H), 6.73-6.69 (m, 3H), 6.56 (m, 1H), 4.56(s, 1H), 4.51 (s, 1H), 3.91-3.76 (m, 4H), 3.04 (m, 4H), 2.77 (s, 2H),2.26 (m, 2H), 2.15 (m, 4H), 1.99-1.85 (m, 6H), 1.39 (t, 2H), 0.94 (s,6H).

Example 444N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamideExample 444A(R)-5-chloro-6-((1-(1,3-difluoropropan-2-yl)pyrrolidin-3-yl)methoxy)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 445B for EXAMPLE 422Bin EXAMPLE 434A.

Example 444BN-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 400E for EXAMPLE 26Cand EXAMPLE 444A for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 12.98 (s, 1H), 8.19 (d, 1H), 7.81 (d, 1H), 7.73(s, 1H), 7.66 (d, 1H), 7.35 (d, 2H), 7.05 (m, 4H), 6.73 (dd, 1H), 6.42(d, 1H), 6.10 (m, 1H), 4.64 (s, 2H), 4.54 (d, 2H), 4.24 (m, 2H), 3.07(s, 4H), 2.89 (s, 2H), 2.74 (m, 4H), 2.56 (m, 2H), 2.20 (m, 6H), 1.98(m, 4H), 1.54 (m, 1H), 1.40 (t, 2H), 0.91 (s, 6H).

Example 445N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamideExample 445A (R)-tert-butyl3-((3-chloro-5-sulfamoylpyridin-2-yloxy)methyl)pyrrolidine-1-carboxylate

This example was prepared by substituting (R)-tert-butyl3-(hydroxymethyl)pyrrolidine-1-carboxylate for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 387B.

Example 445B(R)-5-chloro-6-(pyrrolidin-3-ylmethoxy)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 445A for EXAMPLE 422Ain EXAMPLE 422B.

Example 445C(R)-5-chloro-6-((1-(2,2-difluoroethyl)pyrrolidin-3-yl)methoxy)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 445B for EXAMPLE 422Bin EXAMPLE 422C.

Example 445DN-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 400E for EXAMPLE 26Cand EXAMPLE 445C for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 12.98 (s, 1H), 8.19 (d, 1H), 7.81 (d, 1H), 7.73(s, 1H), 7.66 (d, 1H), 7.35 (d, 2H), 7.05 (m, 4H), 6.72 (dd, 1H), 6.41(d, 1H), 6.10 (m, 2H), 4.23 (m, 2H), 3.07 (s, 4H), 2.82 (m, 5H), 2.62(m, 3H), 2.24 (s, 4H), 2.17 (s, 2H), 1.94 (m, 3H), 1.53 (m, 1H), 1.40(t, 2H), 0.93 (s, 6H).

Example 446Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamideExample 446A2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-4-yloxy]-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-N-(4-((trans-4-methoxycyclohexyl)methylamino)-3-nitrophenylsulfonyl)benzamide

This example was prepared by substituting EXAMPLE 435D for EXAMPLE 1Eand EXAMPLE 311B for EXAMPLE 1F in EXAMPLE 1G.

Example 446BTrans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 446A for EXAMPLE 435Ein EXAMPLE 435F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 13.08 (bs,1H), 8.53 (t, 1H), 8.37 (d, 1H), 7.84 (d, 1H), 7.53 (m, 2H), 7.35 (d,2H), 7.09 (d, 2H), 7.05 (d, 2H), 6.94 (d, 1H), 6.79 (m, 1H), 6.51 (dd,1H), 6.18 (m, 1H), 3.23 (s, 3H), 3.17-3.00 (m, 5H), 2.78 (bs, 2H),2.30-2.13 (m, 8H), 2.02 (m, 2H), 1.97, (bs, 2H), 1.80 (m, 2H), 1.60 (m,1H), 1.40 (t, 2H), 1.07 (m, 4H), 0.93 (s, 6H).

Example 4474-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamideExample 447AN-{4-{4-[2-(4-Chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-4-yloxy]-benzoyl}-4-([1,4]dioxan-2-ylmethoxy)-3-nitrobenzenesulfonamide

This example was prepared by substituting EXAMPLE 435D for EXAMPLE 1Eand EXAMPLE 297A for EXAMPLE 1F in EXAMPLE 1G.

Example 447B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 447A for EXAMPLE 435Ein EXAMPLE 435F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 13.04 (bs,1H), 8.07 (bs, 1H), 7.78 (t, 2H), 7.59 (d, 1H), 7.36 (d, 2H), 7.25 (d,1H), 7.08 (d, 2H), 7.06 (d, 2H), 6.77 (d, 1H), 6.48 (bs, 1H), 6.15 (m,1H), 4.20 (t, 2H), 3.92-3.76 (m, 3H), 3.65 (m, 2H), 3.48 (td, 2H), 3.14(bs, 4H), 2.80 (m, 2H), 2.38-2.13 (m, 6H), 1.97 (bs, 2H), 1.40 (t, 2H),0.94 (s, 6H).

Example 448N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamideExample 448A5-chloro-6-(1-cyclopropyl-piperidin-4-ylamino)-pyridine-3-sulfonic acidamide

This example was prepared by substituting1-cyclopropyl-piperidin-4-ylamine for1-(2-methoxy-ethyl)-piperidin-4-ylamine and EXAMPLE 387A for4-chloro-3-nitrobenzenesulfonamide in EXAMPLE 189A.

Example 448B5-Chloro-6-(1-cyclopropyl-piperidin-4-ylamino)-pyridine-3-sulfonic acid4-{4-[2-(4-chloro-phenyl)-4,4-dimethyl-cyclohex-1-enylmethyl]-piperazin-1-yl}-2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazol-4-yloxy]-benzoylamide

This example was prepared by substituting EXAMPLE 435D for EXAMPLE 1Eand EXAMPLE 448A for EXAMPLE 1F in EXAMPLE 1G.

Example 448CN-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 448B for EXAMPLE 435Ein EXAMPLE 435F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 13.03 (bs,1H), 8.18 (d, 1H), 7.79 (bs, 1H), 7.65-7.58 (m, 2H), 7.36 (d, 2H), 7.33(m, 1H), 7.10 (d, 2H), 7.06 (d, 2H), 6.74 (dd, 1H), 6.43 (bs, 1H), 6.19(m, 1H), 3.95 (m, 1H), 3.08 (m, 4H), 2.96 (m, 2H), 2.75 (bs, 2H),2.37-2.10 (m, 9H), 1.97 (bs, 2H), 1.78 (m, 2H), 1.56 (m, 2H), 1.40 (t,2H), 0.93 (s, 6H), 0.42 (d, 2H), 0.33 (bs, 2H).

Example 4492-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamideExample 449A5-chloro-6-(1-cyclopropylpiperidin-4-ylamino)pyridine-3-sulfonamide

A mixture of EXAMPLE 387A (0.4 g), 1-cyclopropylpiperidin-4-amine (0.3g) and N,N-diisopropylethylamine (0.37 mL) in dioxane (3 mL) was heatedat 100° C. for 18 hours. The crude product was isolated by concentrationand was purified on silica gel, which was eluted with ethyl acetate togive the title compound.

Example 449B2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide

This example was prepared by substituting EXAMPLE 449A for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.22 (m, 1H), 8.55 (s,1H), 8.47 (s, 1H), 8.00 (d, 1H), 7.54 (d, 1H), 7.44 (d, 2H), 7.25 (m,1H), 7.19 (m, 1H), 7.07 (d, 2H), 7.01 (m, 1H), 6.68 (m, 2H), 5.35 (m,2H), 4.22 (m, 1H), 3.04-2.95 (m, 6H), 2.77 (s, 2H), 2.29-2.24 (m, 4H),2.14 (m, 4H), 2.03 (m, 2H), 1.97 (s, 2H), 1.70 (m, 2H), 1.52 (m, 1H),1.38 (t, 2H), 0.94 (s, 6H), 0.35 (m, 4H).

Example 4502-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 336A for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅5) δ 9.24 (m, 1H), 8.81 (m,1H), 8.56 (s, 1H), 8.37 (dd, 1H), 8.03 (d, 1H), 7.52 (d, 1H), 7.44 (d,2H), 7.21 (m, 1H), 7.11 (m, 1H), 7.07 (d, 2H), 6.92 (d, 1H), 6.71 (m,2H), 5.33 (m, 2H), 3.94 (m, 2H), 3.78 (m, 1H), 3.73-3.66 (m, 2H), 3.58(m, 1H), 3.51-3.36 (m, 3H), 3.03 (m, 4H), 2.77 (s, 2H), 2.26 (m, 2H),2.15 (m, 4H), 1.97 (s, 2H), 1.39 (t, 2H), 0.94 (s, 6H).

Example 4512-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 451A4-(1-cyclopropylpiperidin-4-ylamino)-3-nitrobenzenesulfonamide

To a solution of 4-fluoro-3-nitrobenzenesulfonamide (1.26 g) and1-cyclopropylpiperidin-4-amine (0.802 g) in tetrahydrofuran (20 mL) wasadded N,N-diisopropylethylamine (2.22 g) and 4-dimethylaminopyridine (35mg). The mixture was heated at reflux for 18 hours and upon cooling wasdiluted with ethyl acetate (200 mL) and aqueous NaHCO₃. The crudeproduct was isolated by concentration of the organic layer and waspurified on silica gel, which was eluted with 5% methanolic ammonia inmethylene chloride to give the title compound.

Example 451B2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 451 A for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.26 (m, 1H), 8.59 (s,1H), 8.46 (d, 1H), 8.42 (dd, 1H), 8.01 (d, 1H), 7.53 (d, 1H), 7.43 (d,2H), 7.25 (d, 1H), 7.17 (d, 1H), 7.07 (d, 2H), 6.96 (d, 1H), 6.72-6.67(m, 2H), 5.48 (m, 2H), 3.54 (m, 1H), 3.03 (m, 4H), 2.90 (m, 2H), 2.76(s, 2H), 2.37 (m, 2H), 2.25 (m, 2H), 2.14 (m, 4H), 1.98-1.91 (m, 4H),1.56 (m, 3H), 1.38 (t, 2H), 0.94 (s, 6H), 0.42 (m, 4H).

Example 452Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 204A for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.27 (m, 1H), 8.59 (s,1H), 8.42 (dd, 1H), 8.36 (d, 1H), 8.01 (d, 1H), 7.53 (d, 1H), 7.43 (d,2H), 7.25 (m, 1H), 7.17 (m, 1H), 7.07 (d, 2H), 6.95 (d, 1H), 6.71 (d,2H), 6.33 (m, 2H), 3.76 (m, 4H), 3.40 (m, 1H), 3.03 (m, 4H), 2.76 (s,2H), 2.52 (m, 4H), 2.25 (m, 3H), 2.14 (m, 4H), 2.07 (m, 2H), 1.97 (m,2H), 1.89 (m, 2H), 1.42-1.21 (m, 6H), 0.94 (s, 6H).

Example 4532-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 174A for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.25 (m, 2H), 8.59 (s,1H), 8.44 (m, 1H), 8.00 (d, 1H), 7.68 (d, 1H), 7.53 (d, 1H), 7.43 (d,2H), 7.25 (m, 1H), 7.17 (m, 1H), 7.06 (d, 2H), 6.72-6.67 (m, 2H), 6.36(m, 1H), 2.02 (m, 4H), 2.93 (m, 4H), 2.76 (s, 2H), 2.74-2.61 (m, 2H),2.35-2.22 (m, 5H), 2.19 (s, 3H), 2.16-2.10 (m, 4H), 1.97 (m, 2H), 1.38(t, 2H), 0.94 (s, 6H).

Example 4542-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 88A for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.28 (m, 1H), 8.66 (m,1H), 8.58 (s, 1H), 8.40 (dd, 1H), 8.02 (d, 1H), 7.53 (d, 1H), 7.44 (d,2H), 7.24 (m, 1H), 7.15 (m, 1H), 7.07 (d, 2H), 6.89 (d, 1H), 6.73-6.69(m, 2H), 5.86 (m, 2H), 3.17 (t, 2H), 3.01-3.04 (m, 4H), 2.86 (m, 2H),2.77 (s, 2H), 2.25 (m, 5H), 2.14 (m, 4H), 1.96-1.97 (s, 2H), 1.92 (m,2H), 1.70 (m, 2H), 1.60 (m, 1H), 1.48-1.37 (m, 4H), 0.94 (s, 6H).

Example 4552-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({(2R)-4-[2-(2-methoxyethoxy)ethyl]morpholin-2-yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamideExample 455A(R)-4-((4-(2-(2-methoxyethoxy)ethyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting EXAMPLE 437B for EXAMPLE 415Band 2-(2-methoxyethoxy)ethyl bromide for 2,2-difluoroethyl iodide inEXAMPLE 415C.

Example 455B2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({(2R)-4-[2-(2-methoxyethoxy)ethyl]morpholin-2-yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamide

This example was prepared by substituting EXAMPLE 455A for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.24 (d, 1H), 8.85 (t,1H), 8.56 (s, 1H), 8.36 (dd, 1H), 8.03 (d, 1H), 7.51 (d, 1H), 7.44 (d,2H), 7.24 (m, 2H), 7.12 (d, 1H), 7.07 (d, 2H), 6.91 (d, 1H), 6.73-6.68(m, 2H), 3.93-3.86 (m, 2H), 3.72-3.61 (m, 5H), 3.53 (m, 2H), 3.48-3.40(m, 2H), 3.28 (s, 3H), 3.03 (m, 4H), 2.95 (d, 1H), 2.77 (s, 2H), 2.70(d, 1H), 2.69 (t, 2H), 2.27-2.10 (m, 8H), 1.97 (s, 2H), 1.38 (t, 2H),0.94 (s, 6H).

Example 4562-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 412C for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.29 (d, 1H), 8.73 (t,1H), 8.58 (s, 1H), 8.42 (dd, 1H), 7.99 (d, 1H), 7.52 (d, 1H), 7.43 (d,2H), 7.24 (m, 2H), 7.17 (d, 1H), 7.07 (d, 2H), 6.94 (d, 1H), 6.72 (d,1H), 6.69 (dd, 1H), 3.22 (t, 2H), 3.03 (m, 4H), 2.76 (s, 2H), 2.25 (m,2H), 2.13 (m, 6H), 1.97 (s, 2H), 1.85-1.70 (m, 5H), 1.38 (t, 2H),1.36-1.33 (m, 2H), 0.94 (s, 6H).

Example 457N-[(4-{[(4-acetylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamideExample 457A4-((4-acetylmorpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

A solution of EXAMPLE 415B (145 mg) andN-ethyl-N-isopropylpropan-2-amine (120 μl) in anhydrous dichloromethane(5 mL) and N,N-dimethylformamide (2 mL) was cooled with an ice bath andacetic anhydride (56 μl) was added dropwise. The mixture was stirred atroom temperature for 3 hours and concentrated to dryness. The residuewas triturated with water. The resulting solid was dried under vacuum togive the title compound.

Example 457BN-[(4-{[(4-acetylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide

This example was prepared by substituting EXAMPLE 457A for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.24 (d, 1H), 8.83 (t,1H), 8.56 (s, 1H), 8.38 (dd, 1H), 8.03 (d, 1H), 7.51 (d, 1H), 7.43 (d,2H), 7.24 (m, 2H), 7.09 (d, 1H), 7.07 (d, 2H), 6.91 (dd, 1H), 6.72 (m,2H), 3.89 (m, 1H), 3.80-3.70 (m, 1H), 3.60-3.40 (m, 4H), 3.06 (m, 1H),3.03 (m, 4H), 2.77 (s, 2H), 2.70 (m, 1H), 2.26 (m, 2H), 2.18-2.13 (m,5H), 2.09 (s, 3H), 1.97 (s, 2H), 1.38 (t, 2H), 0.94 (s, 6H).

Example 4582-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methylsulfonyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamideExample 458A4-((4-(methylsulfonyl)morpholin-2-yl)methylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting methanesulfonyl chloride foracetic anhydride in EXAMPLE 457A.

Example 458B2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methylsulfonyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide

This example was prepared by substituting EXAMPLE 458A for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.23 (d, 1H), 8.85 (t,1H), 8.57 (s, 1H), 8.37 (dd, 1H), 8.01 (d, 1H), 7.52 (d, 1H), 7.43 (d,2H), 7.24 (m, 2H), 7.15 (d, 1H), 7.07 (d, 2H), 6.97 (d, 1H), 6.72 (m,2H), 4.00-3.90 (m, 3H), 3.68-3.59 (m, 3H), 3.58-3.48 (m, 1H), 3.06-3.02(m, 7H), 2.98-2.89 (m, 2H), 2.77 (s, 2H), 2.25 (m, 2H), 2.14 (m, 4H),1.97 (s, 2H), 1.38 (t, 2H), 0.94 (s, 6H).

Example 4594-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-({4-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamideExample 459A tert-butyl4-fluoro-4-((5-sulfamoyl-3-(trifluoromethyl)pyridin-2-yloxy)methyl)piperidine-1-carboxylate

This example was prepared by substituting EXAMPLE 410E for EXAMPLE 329Aand EXAMPLE 419A for (tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 329B.

Example 459B6-((4-fluoropiperidin-4-yl)methoxy)-5-(trifluoromethyl)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 459A for EXAMPLE 422Ain EXAMPLE 422B.

Example 459C6-((1-(1,3-difluoropropan-2-yl)-4-fluoropiperidin-4-yl)methoxy)-5-(trifluoromethyl)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 459B for EXAMPLE 422Bin EXAMPLE 434A.

Example 459D4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-({4-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 400E for EXAMPLE 26Cand EXAMPLE 459C for EXAMPLE 1F in EXAMPLE 177. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 12.94 (d, 1H), 8.40 (d, 1H), 8.11 (d, 1H), 7.68(m, 2H), 7.35 (d, 2H), 7.06 (d, 2H), 6.99 (d, 2H), 6.71 (dd, 1H), 6.39(d, 1H), 6.06 (t, 1H), 4.67 (d, 2H), 4.55 (d, 2H), 4.47 (d, 2H), 3.07(m, 5H), 2.74 (m, 6H), 2.19 (m, 6H), 1.90 (m, 6H), 1.40 (t, 2H), 0.93(s, 6H).

Example 4604-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide

The title compound was prepared as described in EXAMPLE 177 by replacingEXAMPLE 26C with EXAMPLE 18G. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ12.87 (s, 1H), 11.60 (s, 1H), 8.58 (s, 1H), 8.47 (d, 1H), 8.11 (s, 1H),7.81-7.91 (m, 1H), 7.76 (dd, 1H), 7.59-7.66 (m, 1H), 7.48 (d, 1H), 7.34(d, 2H), 7.00-7.11 (m, 5H), 6.73 (dd, 1H), 6.67 (dd, 1H), 6.08 (d, 1H),3.85 (dd, 2H), 3.20-3.30 (m, 4H), 3.04 (s, 4H), 2.77 (s, 2H), 2.17 (d,6H), 1.96 (s, 2H), 1.81-1.92 (m, 1H), 1.55-1.66 (m, 2H), 1.39 (t, 2H),1.17-1.32 (m, 2H), 0.93 (s, 6H).

Example 4614-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(2-tetrahydrofuran-2-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamideExample 461A5-chloro-6-(2-(tetrahydrofuran-2-yl)ethoxy)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 387A for EXAMPLE 329Aand 2-(tetrahydrofuran-2-yl)ethanol for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 329B.

Example 461B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(2-tetrahydrofuran-2-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 461A for EXAMPLE 1Fand EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177C. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 13.08 (s, 1H), 8.27 (d, J=2.17 Hz, 1H), 7.83 (d,J=1.83 Hz, 1H), 7.80 (s, 1H), 7.58 (d, J=8.85 Hz, 1H), 7.36 (d, J=8.54Hz, 2H), 7.03-7.10 (m, 4H), 6.79 (dd, J=9, 2.29 Hz, 1H), 6.54 (d, J=1.53Hz, 1H), 6.13 (d, J=7.02 Hz, 1H), 4.41-4.47 (m, 2H), 3.91-3.94 (m, 1H),3.71-3.80 (m, 1H), 3.56-3.63 (m, 2H), 3.25 (br s, 2H), 2.33 (br s, 2H),2.16-2.18 (m, 2H), 1.92-2.01 (m, 5H), 1.80-1.86 (m, 2H), 1.47-1.53 (m,1H), 1.42 (t, J=6.26 Hz, 2H), 0.94 (s, 6H).

Example 462Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyanocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamideExample 462A 2-(trans-4-(aminomethyl)cyclohexyl)acetonitrile

To a solution oftert-butyl(trans-4-(cyanomethyl)cyclohexyl)methylcarbamate (500 mg) indichloromethane (5 mL) was slowly added trifluoroacetic acid (3 mL) at0° C. The mixture was warmed to room temperature, stirred for 1 hour.The title compound was obtained by concentration.

Example 462B4-((trans-4-cyanocyclohexyl)methylamino)-3-nitrobenzenesulfonamide

This example was prepared by substituting EXAMPLE 462A for(tetrahydropyran-4-yl)methylamine in EXAMPLE 1F.

Example 462CTrans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyanocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide

This example was prepared by substituting EXAMPLE 462B for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.29 (d, 1H), 8.67 (t,1H), 8.59 (s, 1H), 8.41 (dd, 1H), 7.98 (d, 1H), 7.53 (d, 1H), 7.43 (d,2H), 7.25 (m, 1H), 7.19 (m, 1H), 7.07 (d, 2H), 6.91 (d, 1H), 6.73-6.68(m, 2H), 5.24 (m, 2H), 3.13 (t, 2H), 3.03 (m, 4H), 2.76 (s, 2H), 2.43(m, 1H), 2.25 (m, 2H), 2.13 (m, 4H), 1.99-1.94 (m, 4H), 1.77 (m, H),1.59 (m, 1H), 1.46 (m, 2H), 1.38 (t, 2H), 0.99-0.90 (m, 8H).

Example 4632-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamideExample 463A (4,4-difluorocyclohexyl)methanol

To a slurry of lithium aluminum hydride (0.24 g) in diethyl ether (15mL) was added dropwise ethyl 4,4-difluorocyclohexanecarboxylate (1.0 g)in diethyl ether (2 mL). The reaction heated at reflux under nitrogenfor 4 hours. The reaction was cooled to 0° C., followed by the carefuladdition of water (0.24 mL), 4N aqueous NaOH (0.24 mL), and water (0.72mL). The reaction was diluted with diethyl ether (40 mL) and stirredwith sodium sulfate for 30 minutes. The mixture was filtered thoughdiatomaceous earth and the filtrate was concentrated to provide thetitle compound.

Example 463B5-chloro-6-((4,4-difluorocyclohexyl)methoxy)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 463A for(tetrahydro-2H-pyran-4-yl)methanol and EXAMPLE 387A for EXAMPLE 329A inEXAMPLE 329B.

Example 463C2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide

This example was prepared by substituting EXAMPLE 463B for EXAMPLE 428Din EXAMPLE 428E. ¹H NMR (500 MHz, pyridine-d₅) δ 9.15 (d, 1H), 8.69 (m,1H), 8.59 (s, 1H), 7.99 (d, 1H), 7.53 (d, 1H), 7.44 (d, 2H), 7.24 (m,1H), 7.16 (m, 1H), 7.07 (d, 2H), 6.70 (m, 2H), 5.45 (m, 2H), 4.22 (d,2H), 3.04 (m, 4H), 2.77 (s, 2H), 2.26 (m, 2H), 2.16-2.08 (m, 6H), 1.97(s, 2H), 1.86-1.68 (m, 5H), 1.47-1.36 (m, 4H), 0.94 (m, 6H).

Example 464N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamideExample 464A3-chloro-4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide

This example was prepared by substituting 3,4-dichlorobenzenesulfonamidefor EXAMPLE 329A and EXAMPLE 306C for (tetrahydro-2H-pyran-4-yl)methanolin EXAMPLE 329B.

Example 464BN-(3-chloro-4-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)phenylsulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-enyl)methyl)piperazin-1-yl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 435D for EXAMPLE 1Eand EXAMPLE 464A for EXAMPLE 1F in EXAMPLE 1G.

Example 464CN-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 464B for EXAMPLE 435Ein EXAMPLE 435F. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 13.15 (s, 1H),11.74-11.31 (m, 1H), 7.85 (s, 1H), 7.67 (d, 1H), 7.62-7.49 (m, 2H), 7.35(d, 2H), 7.22-7.09 (m, 3H), 7.05 (d, 2H), 6.80 (d, 1H), 6.53 (s, 1H),6.23 (d, 1H), 4.26 (d, 2H), 3.79 (d, 2H), 3.62 (dd, 2H), 3.17 (s, 4H),2.77 (d, 2H), 2.22 (d, 6H), 1.88 (dd, 6H), 1.40 (t, 2H), 0.94 (s, 6H).

Example 465N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamideExample 465A methyl2-(1H-indazol-4-yloxy)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)benzoate

This example was prepared by substituting EXAMPLE 400C for tert-butylpiperazine-1-carboxylate and EXAMPLE 145E for EXAMPLE 27C in EXAMPLE 1A.

Example 465B methyl4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yloxy)benzoate

This example was prepared by substituting EXAMPLE 465A for EXAMPLE 400Din EXAMPLE 435C.

Example 465C4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yloxy)benzoicacid

This example was prepared by substituting EXAMPLE 465B for EXAMPLE 175Din EXAMPLE 175E.

Example 465DN-(5-chloro-6-((4-fluorotetrahydro-2H-pyran-4-yl)methoxy)pyridin-3-ylsulfonyl)-4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 465C for EXAMPLE 27Gand EXAMPLE 404A for EXAMPLE 1F in EXAMPLE 27H.

Example 465EN-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 465D for EXAMPLE 435Ein EXAMPLE 435F, except here the final compound was purified bypreparative HPLC using a C18 column, 250×50 mm, 10, and eluting with agradient of 20-100% CH₃CN vs. 0.1% trifluoroacetic acid in water,followed by column chromatography eluting with 98/2dichloromethane/methanol. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 13.13(s, 1H), 8.28 (d, 1H), 7.90 (d, 1H), 7.83 (s, 1H), 7.58 (d, 1H), 7.39(d, 2H), 7.17 (d, 2H), 7.08 (m, 2H), 6.82 (dd, 1H), 6.57 (d, 1H), 6.14(d, 1H), 4.52 (d, 2H), 4.15 (s, 2H), 3.80 (m, 2H), 3.60 (m, 2H), 3.20 (vbr m, 4H), 2.98 (v br s, 2H), 2.35 (v br m, 4H), 2.18 (s, 2H), 1.87 (m,4H), 1.20 (s, 6H).

Example 4664-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-tetrahydro-2H-pyran-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamideExample 466A5-bromo-6-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)pyridine-3-sulfonamide

This example was prepared by substituting2-(tetrahydro-2H-pyran-4-yl)ethanol for(tetrahydro-2H-pyran-4-yl)methanol in EXAMPLE 329B.

Example 466B5-cyano-6-(2-(tetrahydro-2H-pyran-4-yl)ethoxy)pyridine-3-sulfonamide

This example was prepared by substituting EXAMPLE 466A for EXAMPLE 329Ain EXAMPLE 333A.

Example 466C4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-tetrahydro-2H-pyran-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide

This example was prepared by substituting EXAMPLE 466B for EXAMPLE 1Fand EXAMPLE 400E for EXAMPLE 26C in EXAMPLE 177C. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 13.04 (s, 1H), 8.48 (d, 1H), 8.13 (s, 1H), 7.75(s, 1H), 7.62 (d, 1H), 7.37 (d, 2H), 7.01-7.08 (m, 4H), 6.76 (dd, 1H),6.51 (d, 1H), 6.08 (d, 1H), 4.47 (t, 2H), 3.81-3.85 (m, 2H), 3.71-3.80(m, 1H), 2.18 (m, 2H), 1.99 (m, 2H), 1.62-1.72 (m, 5H), 1.42 (t, 2H),1.23 (m, 2H), 0.94 (s, 6H).

Example 4674-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamideExample 467A4-((1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-ylamino)-3-nitrobenzenesulfonamide

This EXAMPLE was prepared by substituting(1R,3R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-amine for1-(2-methoxy-ethyl)-piperidin-4-ylamine in EXAMPLE 189A.

Example 467B4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide

This EXAMPLE was prepared by substituting EXAMPLE 26C for EXAMPLE 1E andEXAMPLE 467A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (500 MHz,dimethylsulfoxide-d₆) δ 11.47 (br s, 1H), 11.17 (s, 1H), 9.43 (br s,1H), 8.69 (d, 1H), 8.62 (d, 1H), 7.90 (dd, 1H), 7.52 (d, 1H), 7.40 (m,3H), 7.15 (d, 1H), 7.06 (m, 3H), 6.85 (dd, 1H), 6.68 (m, 1H), 6.39 (t,1H), 6.19 (br s, 1H), 4.01 (m, 1H), 3.91 (m, 2H), 3.58 (m, 3H), 3.01 (m,3H), 2.73 (m, 5H), 2.32 (m, 6H), 2.16 (m, 6H), 2.0 (m, 2H), 1.45 (m,2H), 0.94 (s, 6H).

Example 468N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxy-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamideExample 468A methyl2-phenoxy-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzoate

1,4-dioxa-8-azaspiro[4.5]decane (1.18 g), methyl4-fluoro-2-phenoxybenzoate (1.85 g), and K₂CO₃ (1.14 g) was stirred at125° C. in dimethylsulfoxide (25 mL) for 24 hours. The mixture wascooled, poured into 300 mL water, extracted three times with ether, andthe ether extracts were combined, rinsed three times with water, andbrine, and concentrated. The residue was chromatographed on silica gelusing 10-30% ethyl acetate in hexanes as eluent to give the titlecompound.

Example 468B methyl 4-(4-oxopiperidin-1-yl)-2-phenoxybenzoate

EXAMPLE 468A (23.7 g) was heated to 80° C. in a mixture of acetic acid(30 mL), tetrahydrofuran (40 mL) and water (30 mL) for 24 hours. Themixture was cooled and concentrated. The crude product waschromatographed on silica gel using 25% ethyl acetate in hexanes as theeluent to give the title compound.

Example 468C methyl2-phenoxy-4-(4-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ylamino)piperidin-1-yl)benzoate

EXAMPLE 468B (0.99 g) and(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-amine (0.51 mL) wererefluxed in 200 mL methanol under a Dean-Stark trap for 24 hours. Thesolvent was boiled off to a volume of 75 mL, and the mixture was cooledto room temperature. NaBH₄ (0.115 g) was added and the mixture wasstirred for 30 minutes. The reaction was quenched with 10 mL water,partially concentrated, and chromatographed on silica gel using 1%triethylamine in ethyl acetate as eluent to give the title compound.

Example 468D methyl2-phenoxy-4-(4-(3-phenyl-N-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)propanamido)piperidin-1-yl)benzoate

EXAMPLE 468C (320 mg), 3-phenylpropanoyl chloride (0.113 mL), andtriethylamine (0.116 mL) were stirred in dichloromethane (15 mL) for 24hours. The reaction mixture was partially concentrated and the residuewas chromatographed on silica gel using 20% ethyl acetate in hexanes aseluent to give the title compound.

Example 468E2-phenoxy-4-(4-(3-phenyl-N-((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)propanamido)piperidin-1-yl)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 468D for EXAMPLE 1D inEXAMPLE 1E.

Example 468FN-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxy-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 468E for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.32 (m, 2H), 7.64(m, 2H), 7.11-7.29 (m, 6H), 6.95 (dd, 1H), 6.89 (dd, 1H), 6.70 (m, 3H),6.32 (m, 1H), 3.85 (m, 3H), 3.70 (m, 3H), 2.91 (m, 6H), 2.65-2.80 (m,6H), 1.91 (s, 6H), 1.61 (m, 4H), 1.16-1.36 (m, 4H), 1.11 (m, 6H), 0.95(m, 4H), 0.87 (d, 2H).

Example 469N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxy-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 468E for EXAMPLE 1Eand EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.72 (m, 1H), 8.44 (d, 1H), 7.73 (dd, 1H), 7.54(m, 1H), 7.12-7.28 (m, 6H), 7.05 (dd, 1H), 6.95 (dd, 1H), 6.82 (d, 1H),6.74 (m, 2H), 6.34 (m, 1H), 3.77 (m, 2H), 3.63 (m, 4H), 3.10 (m, 4H),3.05 (m, 4H), 2.78 (m, 6H), 1.75-2.10 (m, 8H), 1.55 (m, 2H), 1.40 (m,2H), 1.19 (m, 6H), 1.01 (m, 2H), 0.95 (m, 2H), 0.88 (d, 2H).

Example 470N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxy-4-(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamideExample 470A methyl2-phenoxy-4-(4-((3-phenylpropyl)((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)amino)piperidin-1-yl)benzoate

EXAMPLE 468C (320 mg), 3-phenylpropanal (111 mg), and NaBH(OAc)₃ (205mg) were stirred in dichloromethane (15 mL) for 24 hours. The reactionmixture was chromatographed on silica gel using 20% ethyl acetate inhexanes as eluent to give the title compound.

Example 470B2-phenoxy-4-(4-((3-phenylpropyl)((1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)amino)piperidin-1-yl)benzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 470A for EXAMPLE 1D inEXAMPLE 1E.

Example 470CN-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxy-4-(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 470B for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (300 MHz, dimethylsulfoxide-d₆) δ 8.57 (m, 1H), 8.47(d, 1H), 7.50 (m, 1H), 7.32 (m, 1H), 7.12-7.31 (m, 7H), 6.99 (dd, 1H),6.81 (m, 3H), 6.37 (d, 1H), 4.44 (t, 1H), 3.84 (m, 4H), 3.37 (m, 2H),3.25 (m, 2H), 3.06 (m, 2H), 2.70 (m, 4H), 2.57 (m, 4H), 1.82 (m, 2H),1.77 (m, 4H), 1.52-1.71 (m, 8H), 1.25 (m, 3H), 1.15 (s, 3H), 0.95 (d,2H), 0.93 (s, 3H), 0.74 (d, 2H).

Example 471N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxy-4-(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 470B for EXAMPLE 1Eand EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 1G. ¹H NMR (300 MHz,dimethylsulfoxide-d₆) δ 8.68 (m, 1H), 8.40 (d, 1H), 7.70 (dd, 1H), 7.55(d, 1H), 7.11-7.29 (m, 7H), 7.01 (dd, 1H), 6.95 (dd, 1H), 6.76 (d, 2H),6.34 (m, 1H), 3.75 (m, 2H), 3.61 (m, 4H), 3.43 (m, 4H), 3.05 (m, 6H),2.75 (m, 2H), 2.60 (m, 2H), 2.41 (m, 4H), 2.15 (m, 1H), 1.82 (m, 4H),1.69 (m, 2H), 1.51 (m, 1H), 1.18 (m, 8H), 0.96 (m, 1H), 0.94 (s, 3H).

Example 4724-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)piperazin-1-yl]-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamideExample 472A

Ethyl 4-fluoro-2-phenoxybenzoate (600 mg) and piperazine (596 mg) weredissolved in anhydrous dimethyl sulfoxide and heated at 130° C.overnight. The reaction mixture was cooled to room temperature anddiluted with ethyl acetate. The organic phase was washed with water andbrine, dried over anhydrous sodium sulfate, filtered, and concentratedto afford the title compound.

Example 472B

EXAMPLE 472A (400 mg), 1-(bromomethyl)-2-nitrobenzene (277 mg) andsodium carbonate (408 mg) were suspended in anhydrousN,N-dimethylformamide (20 mL). The reaction mixture was stirred at roomtemperature for 4 hours. The reaction mixture was diluted with ethylacetate. The organic phase was washed with water and brine, dried overanhydrous sodium sulfate, filtered, and concentrated. Flash columnpurification with 10-40% ethyl acetate/hexane to afford the titlecompound.

Example 472C

A solution of EXAMPLE 472B (0.6 g) in methanol (20 ml) was added toRa—Ni, solvent washed (0.480 g) in a 250 mL pressure bottle and stirredfor 3 hours at 30 psi at room temperature. The mixture was filteredthrough a nylon membrane and concentrated to afford the product.

Example 472D

This EXAMPLE was prepared by substituting(1R,5S)-8-methyl-8-azabicyclo[3.2.1]octan-3-one for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 472C for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 472E

This EXAMPLE was prepared by substituting EXAMPLE 472D for EXAMPLE 175Din EXAMPLE 175E.

Example 472F4-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)piperazin-1-yl]-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide

This EXAMPLE was prepared by substituting EXAMPLE 472E for EXAMPLE 27Gand EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.66 (bs, 1H), 9.90 (bs, 1H), 9.56 (s, 1H),8.69 (t, 1H), 8.50 (d, 1H), 7.81 (dd, 1H), 7.54 (d, 1H), 7.22 (m, 5H),7.01 (m, 1H), 6.83 (m, 3H), 6.47 (s, 1H), 3.84 (m, 4H), 3.65 (d, 6H),3.54 (m, 4H), 3.43 (m, 2H), 3.19 (m, 8H), 2.68 (d, 3H), 2.34 (m, 2H),2.25 (m, 4H), 1.99 (m, 4H).

Example 4734-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide

This EXAMPLE was prepared by substituting EXAMPLE 472E for EXAMPLE 27Gin EXAMPLE 27H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.61 (bs, 1H),9.38 (bs, 1H), 8.64 (s, 1H), 8.47 (d, 1H), 7.75 (dd, 1H), 7.55 (d, 1H),7.23 (t, 3H), 7.15 (d, 2H), 6.98 (t, 1H), 6.82 (d, 3H), 6.47 (s, 2H),3.85 (m, 6H), 3.31 (m, 12H), 2.68 (d, 3H), 2.06 (m, 9H), 1.62 (m, 2H),1.29 (m, 2H).

Example 4744-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamideExample 474A

2-Fluorobenzaldehyde (264 mg), (1S,5S)-3-azabicyclo[3.2.2]nonane (500mg) and sodium carbonate (846 mg) were suspended in anhydrousdimethylsulfoxide (3 mL). The reaction mixture was heated at 135° C.overnight. The reaction mixture was cooled to room temperature anddiluted with ethyl acetate. The organic phase was washed with water andbrine, dried over anhydrous sodium sulfate, filtered, and concentrated.Flash column purification with 0-10% ethyl acetate/hexane provided thetitle compound.

Example 474B

This EXAMPLE was prepared by substituting EXAMPLE 474A for4′-chlorobiphenyl-2-carboxaldehyde and EXAMPLE 113A for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 474C

This EXAMPLE was prepared by substituting EXAMPLE 474B for EXAMPLE 175Din EXAMPLE 175E.

Example 474D4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide

This EXAMPLE was prepared by substituting EXAMPLE 474C for EXAMPLE 27Gin EXAMPLE 27H. ¹H NMR (400 MHz, dimethylsulfoxide-d₆) δ 11.74 (bs, 1H),8.64 (t, 1H), 8.47 (d, 1H), 7.76 (dd, 1H), 7.54 (m, 2H), 7.43 (d, 2H),7.23 (m, 3H), 7.15 (d, 1H), 6.98 (t, 1H), 6.83 (m, 3H), 6.53 (d, 1H),4.45 (bs, 2H), 3.87 (m, 4H), 3.30 (m, 6H), 3.06 (m, 8H), 1.89 (m, 7H),1.64 (m, 6H), 1.29 (m, 2H).

Example 4754-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 474C for EXAMPLE 27Gand EXAMPLE 163A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.78 (bs, 1H), 8.11 (d, 1H), 7.86 (dd, 1H),7.54 (d, 2H), 7.44 (d, 2H), 7.28 (m, 4H), 7.11 (d, 1H), 7.04 (m, 1H),6.85 (m, 3H), 6.53 (d, 1H), 4.46 (m, 2H), 3.86 (m, 4H), 3.28 (m, 6H),3.10 (m, 4H), 2.98 (d, 4H), 1.97 (s, 2H), 1.84 (m, 5H), 1.64 (m, 6H),1.26 (m, 2H).

Example 4764-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 474C for EXAMPLE 27Gand EXAMPLE 2A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.19 (bs, 1H), 9.83 (bs, 1H), 7.52 (m, 6H),7.33 (m, 3H), 7.12 (t, 1H), 6.93 (d, 2H), 6.83 (m, 1H), 6.56 (d, 2H),6.47 (d, 1H), 4.47 (s, 2H), 3.85 (m, 4H), 3.26 (m, 2H), 3.11 (m, 4H),2.96 (m, 6H), 1.97 (s, 2H), 1.81 (m, 6H), 1.64 (m, 7H), 1.22 (m, 2H).

Example 4774-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide

This EXAMPLE was prepared by substituting EXAMPLE 474C for EXAMPLE 27Gand EXAMPLE 7A for EXAMPLE 1F in EXAMPLE 27H. ¹H NMR (400 MHz,dimethylsulfoxide-d₆) δ 11.77 (bs, 1H), 10.04 (bs, 1H), 8.69 (t, 1H),8.50 (d, 1H), 7.81 (dd, 1H), 7.55 (d, 2H), 7.43 (d, 2H), 7.24 (m, 3H),7.15 (d, 1H), 7.01 (t, 1H), 6.84 (m, 3H), 6.52 (d, 1H), 4.44 (s, 2H),3.97 (s, 2H), 3.54 (m, 6H), 3.39 (m, 4H), 3.19 (m, 8H), 2.97 (d, 4H),1.99 (m, 4H), 1.83 (m, 4H), 1.64 (m, 4H).

Example 4784-(4-{2-[(4R,7S)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoinden-5-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamideExample 478A4-(4-Methoxycarbonyl-3-phenoxy-phenyl)-piperazine-1-carboxylic acidtert-butyl ester

This EXAMPLE was prepared by substituting piperazine-1-carboxylic acidtert-butyl ester for EXAMPLE 1B in EXAMPLE 1D.

Example 478B 4-(4-Carboxy-3-phenoxy-phenyl)-piperazine-1-carboxylic acidtert-butyl ester

This EXAMPLE was prepared by substituting EXAMPLE 478A for EXAMPLE 1D inEXAMPLE 1E.

Example 478C4-(4-{3-Nitro-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-benzenesulfonylaminocarbonyl}-3-phenoxy-phenyl)-piperazine-1-carboxylicacid tert-butyl ester

This EXAMPLE was prepared by substituting EXAMPLE 478B for EXAMPLE 1E inEXAMPLE 1G.

Example 478D3-Nitro-N-(2-phenoxy-4-piperazin-1-yl-benzoyl)-4-[(tetrahydro-pyran-4-ylmethyl)-amino]-benzenesulfonamide

This EXAMPLE was prepared by substituting EXAMPLE 478C for EXAMPLE 1A inEXAMPLE 1B to isolate the title compound as the mono trifluoroaceticacid salt.

Example 478E Trifluoromethanesulfonic acid(4R,7S)-(2,3,3a,4,7,7a-hexahydro-1H-4,7-methano-inden-5-yl)ester

(4R,7R)-octahydro-4,7-methano-inden-5-one (2.00 g) was dissolved intetrahydrofuran (25 mL) and cooled to −78° C. using an isopropylalcohol/dry ice bath. Sodium bis(trimethylsilyl)-amide (1M intetrahydrofuran, 14.65 mL) was added slowly. The solution was allowed towarm to room temperature, stirred for one hour, cooled to −78° C. usingan isopropyl alcohol/dry ice bath, andN-phenyltrifluoromethanesulfonimide (5.23 g) was added. The solution wasallowed to warm to room temperature and stir for 16 hours. Hexane wasadded and the solution was stirred at room temperature for one hour,filtered, and the solvent removed under vacuum.

Example 478F(4R,7S)-2-(2,3,3a,4,7,7a-Hexahydro-1H-4,7-methano-inden-5-yl)-benzaldehyde

EXAMPLE 478E (941 mg), 2-formylphenylboronic acid (600 mg), andpotassium phosphate tribasic (1416 mg) were added to tetrahydrofuran (20mL). The solution was degasses and flushed with nitrogen three times.Tetrakis(triphenylphospine)palladium(0) (244 mg) was added and thesolution was heated at 60° C. for 16 hours. The solution was cooled,added to water, and extracted with 50% ethyl acetate (hexanes). Theextract was washed with brine, dried on anhydrous sodium sulfate,concentrated and purified by flash column chromatography on silica gelusing 10% ethyl acetate (hexanes).

Example 478G4-(4-{2-[(4R,7S)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoinden-5-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide

EXAMPLE 478D (200 mg), EXAMPLE 478F (74 mg), and sodium cyanoborohydrideresin (2.15 mmol/g, 144 mg) were added to tetrahydrofuran (3 mL) andacetic acid (0.7 mL) and stirred at room temperature for 16 hours. Thesolution was concentrated on vacuum and purified by flash columnchromatography on silica gel using 5% methanol (dichloromethane) toprovide the title compound as the mono acetic acid salt. ¹H NMR (300MHz, dimethylsulfoxide-d₆) δ 11.94 (bs, 1H), 8.64 (t, 1H), 8.48 (d, 1H),7.76 (dd, 1H), 7.51 (d, 1H), 7.40 (m, 1H), 7.27-7.18 (m, 5H), 7.16 (d,1H), 6.99 (tt, 1H), 6.83 (dt, 2H), 6.78 (dd, 1H), 6.41 (d, 1H), 6.23 (d,1H), 3.87 (dd, 2H), 3.50 (m, 2H), 3.34 (t, 2H), 3.21 (bs, 4H), 2.73 (bs,1H), 2.63 (bs, 1H), 2.46 (m, 4H), 2.11 (m, 2H), 1.95-1.75 (m, 4H), 1.91(s, 3H), 1.66-1.52 (m, 6H), 1.28 (m, 2H), 1.02 (m, 2H), 0.85 (m, 1H).

Example 4794-[4-(2-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamideExample 479A tert-butyl4-(4-(methoxycarbonyl)-3-phenoxyphenyl)piperazine-1-carboxylate

This EXAMPLE was prepared by substituting tert-butylpiperazine-1-carboxylate for EXAMPLE 1B in EXAMPLE 1D.

Example 479B 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-phenoxybenzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 479A for EXAMPLE 1D inEXAMPLE 1E.

Example 479C tert-butyl4-(4-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)-3-phenoxyphenyl)piperazine-1-carboxylate

This EXAMPLE was prepared by substituting EXAMPLE 479B for EXAMPLE 1E inEXAMPLE 1G.

Example 479DN-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)-2-phenoxy-4-(piperazin-1-yl)benzamide

This EXAMPLE was prepared by substituting EXAMPLE 479C for EXAMPLE 1A inEXAMPLE 1B.

Example 479E2-((4-(4-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)-3-phenoxyphenyl)piperazin-1-yl)methyl)phenylboronicacid

EXAMPLE 479D (213 mg), 2-formylphenylboronic acid (54 mg), and sodiumcyanoborohydride resin (2.38 mmol/g, 252 mg) were added totetrahydrofuran (3.5 mL) and acetic acid (1.1 mL), and the solution wasstirred at room temperature for 16 hours. The solution was purified byflash column chromatography on silica gel with 1% acetic acid and 10%methanol in dichloromethane.

Example 479F 8-((5-bromothiophen-2-yl)methyl)-8-azabicyclo[3.2.1]octanehydrochloride

This EXAMPLE was prepared by substituting5-bromothiophene-2-carbaldehyde for 4′-chlorobiphenyl-2-carboxaldehydeand 8-azabicyclo[3.2.1]octane hydrochloride for tert-butylpiperazine-1-carboxylate in EXAMPLE 1A.

Example 479G4-(4-(2-(5-(8-azabicyclo[3.2.1]octan-8-ylmethyl)thiophen-2-yl)benzyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)-2-phenoxybenzamide

EXAMPLE 479E (80 mg), EXAMPLE 479F (42.5 mg),bis(triphenylphosphine)palladium(II) dichloride (7.7 mg), and lithiumhydroxide (10.5 mg) were combined in a mixture of dimethoxyethane (1.6mL), methanol (0.5 mL) and water (0.7 mL) in a microwave vial. Thereaction mixture was heated in a CEM Discover microwave reactor at 150°C. for 15 minutes. The crude material was purified by flashchromatography eluting with a gradient of 1% methanol/dichloromethane to5% methanol/dichloromethane. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ8.33 (m, 2H), 7.64 (m, 2H), 7.44 (m, 1H), 7.39 (m, 1H), 7.32 (m, 2H),7.12 (m, 3H), 6.90 (m, 2H), 6.85 (t, 1H), 6.68 (m, 3H), 6.30 (d, 1H),3.83 (dd, 2H), 3.65 (s, 2H), 3.51 (s, 2H), 3.17 (m, 4H), 3.08 (m, 4H),2.45 (m, 6H), 1.92 (m, 2H), 1.62 (m, 4H), 1.54 (m, 3H), 1.28 (m, 6H).

Example 4804-[4-(2-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzylidene)piperidin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamideExample 480A methyl2-phenoxy-4-(1,4-dioxa-8-azaspiro[4.5]decan-8-yl)benzoate

Methyl 4-fluoro-2-phenoxybenzoate (2 g) and1,4-dioxa-8-azaspiro[4.5]decane (1.279 g) were combined indimethylsulfoxide O (12 mL) in a 250 mL round-bottom flask. Sodiumcarbonate (1.291 g) was added. The reaction flask was sealed and heatedto 130° C. overnight. The reaction mixture was diluted with ethylacetate, washed thoroughly with water and with brine, and dried overMgSO₄, filtered and concentrated to obtain the desired product.

Example 480B methyl 4-(4-oxopiperidin-1-yl)-2-phenoxybenzoate

EXAMPLE 480A was taken up in acetic acid (30%, 20 mL) andtetrahydrofuran (10 mL). The reaction mixture was heated to 75° C.overnight. The volume was reduced under vacuum and the residue wasneutralized with sodium hydroxide solution, and extracted with ethylacetate. The extracts were washed with water and with brine, dried overMgSO₄, filtered and concentrated under vacuum to obtain the desiredproduct.

Example 480C methyl4-(4-(2-bromobenzylidene)piperidin-1-yl)-2-phenoxybenzoate

Dimethylsulfoxide (22.88 mL) with sodium hydride (0.332 g) was heated to70° C. for 1 hour, then cooled to room temperature and(2-bromobenzyl)triphenylphosphonium bromide (3.40 g) was added inseveral portions, and then stirred at room temperature for 1 hour. Asolution of methyl 4-(4-oxopiperidin-1-yl)-2-phenoxybenzoate (1.8 g) indimethylsulfoxide (5.20 mL) was then added and the reaction was heatedto 70° C. over the weekend. The reaction was acidified with 1M aqueousHCl solution and extracted with ether. The combined extracts were washedthoroughly with water and brine, dried over MgSO₄, filtered andconcentrated under vacuum. The residue was purified by flashchromatography eluting with 0-20% ethyl acetate in hexanes.

Example 480D methyl2-phenoxy-4-(4-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylidene)piperidin-1-yl)benzoate

EXAMPLE 480C (259 mg), bis(pinacolato)diboron (206 mg),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane (22 mg), and potassium acetate (159 mg) were combined indimethyl sulfoxide (2.7 mL). The reaction was heated to 90° C. for 36hours. The reaction mixture was diluted with ethyl acetate, washedthoroughly with water and with brine, and dried over MgSO₄, filtered andconcentrated under vacuum. The crude solid was washed with hexanes andwith hexanes/ether (2:1) to obtain the desired product.

Example 480E4-(4-(2-(5-(8-azabicyclo[3.2.1]octan-8-ylmethyl)thiophen-2-yl)benzylidene)piperidin-1-yl)-2-phenoxybenzoicacid

This EXAMPLE was prepared by substituting EXAMPLE 480D for EXAMPLE 479Ein EXAMPLE 479G.

Example 480F4-(4-(2-(5-(8-azabicyclo[3.2.1]octan-8-ylmethyl)thiophen-2-yl)benzylidene)piperidin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)-2-phenoxybenzamide

This EXAMPLE was prepared by substituting EXAMPLE 480E for EXAMPLE 1E inEXAMPLE 1G. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.54 (s, 1H), 9.36(br s, 1H), 8.48 (d, 1H), 7.76 (dd, 1H), 7.53 (m, 2H), 7.34 (m, 3H),7.25 (m, 4H), 7.16 (d, 1H), 7.00 (t, 1H), 6.84 (d, 2H), 6.81 (dd, 1H),6.44 (d, 1H), 6.37 (br s, 1H), 4.36 (d, 2H), 3.85 (m, 3H), 3.44 (m, 2H),3.28 (m, 6H), 2.36 (m, 3H), 2.23 (m, 4H), 1.90 (m, 3H), 1.81 (m, 2H),1.62 (m, 5H), 1.47 (m, 1H), 1.29 (m, 2H).

Example 4814-[4-(3-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamideExample 481A3-((4-(4-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonylcarbamoyl)-3-phenoxyphenyl)piperazin-1-yl)methyl)phenylboronicacid

This EXAMPLE was prepared by substituting 3-formylphenylboronic acid for2-formylphenylboronic acid in EXAMPLE 479E.

Example 481B4-(4-(3-(5-(8-azabicyclo[3.2.1]octan-8-ylmethyl)thiophen-2-yl)benzyl)piperazin-1-yl)-N-(3-nitro-4-((tetrahydro-2H-pyran-4-yl)methylamino)phenylsulfonyl)-2-phenoxybenzamide

This EXAMPLE was prepared by substituting EXAMPLE 481A for EXAMPLE 479Ein EXAMPLE 479G. ¹H NMR (500 MHz, dimethylsulfoxide-d₆) δ 11.76 (br s,1H), 9.55 (br s, 1H), 8.55 (t, 1H), 8.46 (d, 1H), 7.75 (m, 2H), 7.54 (m,2H), 7.40 (m, 1H), 7.20 (m, 4H), 6.97 (m, 1H), 6.86 (m, 1H), 6.82 (m,3H), 6.55 (m, 1H), 4.41 (d, 2H), 3.88 (m, 6H), 3.43 (m, 3H), 3.30 (m,6H), 3.06 (m, 6H), 1.90 (m, 4H), 1.65 (m, 5H), 1.30 (m, 3H).

What is claimed is:
 1. A compound having formula I

or a therapeutically acceptable salt, prodrug or salt of prodrugthereof, wherein A¹ is N or C(A²); one or two or three or each of A²,B¹, D¹ and E¹ are independently selected R¹, OR¹, SR¹, S(O)R¹, SO₂R¹,C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹,NHC(O)OR¹, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NHR¹, SO₂N(R)₂, NHSO₂R¹,NHSO₂NHR¹ or N(CH₃)SO₂N(CH₃)R¹, and the remainder are independentlyselected H, F, Cl, Br, I, CN, CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); andY¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂,C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷; or B¹ and Y¹, togetherwith the atoms to which they are attached, are imidazole or triazole;and one or two or each of A², D¹ and E¹ are independently selected R¹,OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NHC(O)NHR¹,N(CH₃)C(O)N(CH₃)R¹, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ orN(CH₃)SO₂N(CH₃)R¹, and the remainder are independently selected H, F,Cl, Br, I, CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); R¹ is R², R³, R⁴ or R;R^(1A) is C₁-C₆-alkyl, C₃-C₆-alkenyl or C₃-C₆-alkynyl; R² is phenylwhich is unfused or fused with arene, heteroarene or R^(2A); R^(2A) iscycloalkane or heterocycloalkane; R³ is heteroaryl which is unfused orfused with benzene, heteroarene or R^(3A); R^(3A) is cycloalkane orheterocycloalkane; R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl, each of which is unfused or fused with arene,heteroarene or R^(4A); R^(4A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁵ is alkyl, alkenyl or alkynyl,each of which is unsubstituted or substituted with one or two or threeindependently selected R⁶, NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷,SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷, C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷, NHSO₂R⁷,NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O),C(O)OH, (O), N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents; R⁶is C₂-C₅-spiroalkyl, each of which is unsubstituted or substituted withOH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) or N(CH₃)₂;R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C); R^(6C) is aziridin-1-yl,azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl, each having one CH₂moiety unreplaced or replaced with O, C(O), CNOH, CNOCH₃, S, S(O), SO₂or NH; R⁷ is R⁸, R⁹, R¹⁰ or R¹¹; R⁸ is phenyl which is unfused or fusedwith arene, heteroarene or R^(8A); R^(8A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁹ is heteroaryl which isunfused or fused with arene, heteroarene or R^(9A); R^(9A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁰ isC₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(10A); R^(10A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R¹¹ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoor three independently selected R¹², OR¹², NHR¹², N(R¹²)₂, C(O)NH₂,C(O)NHR¹², C(O)N(R¹²)₂, OH, (O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F,Cl, Br or I substituents; R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶; R¹³ is phenylwhich is unfused or fused with arene, heteroarene or R^(13A); R^(13A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁴ isheteroaryl, each of which is unfused or fused with arene, heteroarene orR^(14A); R^(14A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene, each of which is unfused or fused with arene,heteroarene or R^(15A); R^(15A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R¹⁶ is alkyl, alkenyl oralkynyl; R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹; R¹⁸ is phenyl which is unfused orfused with arene, heteroarene or R^(18A); R^(18A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁹ is heteroarylwhich is unfused or fused with arene, heteroarene or R^(19A); R^(19A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R²⁰ isC₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(20A); R^(20A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R²¹ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoor three independently selected R²², OR²², NHR²², N(R²²)₂, C(O)NH₂,C(O)NHR²², C(O)N(R²²)₂, OH, (O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F,Cl, Br or I substituents; R²² is R²³, R²⁴ or R²⁵; R²³ is phenyl which isunfused or fused with arene, heteroarene or R^(23A); R^(23A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R²⁴ isheteroarene which is unfused or fused with arene, heteroarene orR^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R²⁵ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N, and each of which is unfused orfused with arene, heteroarene or R^(25A); R^(25A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; Z¹ is R²⁶ or R²⁷,each of which is substituted with R²⁸, R²⁹ or R³⁰, each of which issubstituted with F, Cl, Br, I, CH₂R³⁷, CH(R³¹)(R³⁷),C(R³¹)(R^(31A))(R³⁷), C(O)R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, NHR³⁷ orN(R³²)R³⁷; R²⁶ is phenyl which is unfused or fused with arene orheteroarene; R²⁷ is heteroarene which is unfused or fused with arene orheteroarene; R²⁸ is phenyl which is unfused or fused with arene,heteroarene or R^(28A); R^(28A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene R²⁹ is heteroaryl or R^(29A);R^(29A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R³⁰ is cycloalkyl or cycloalkenyl, each having one ortwo CH₂ moieties unreplaced or replaced with independently selected O,C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moietiesunreplaced or replaced with N, and each of which is unfused or fusedwith arene, heteroarene or R^(30A); R^(30A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R³¹ and R^(31A) areindependently F, Cl, Br or alkyl or are taken together and areC₂-C₅-spiroalkyl; R³² is R³³, C(O)R³³ or C(O)OR³³; R³³ is R³⁴ or R³⁵;R³⁴ is phenyl which is unfused or fused with aryl, heteroaryl orR^(34A); R^(34A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R³⁵ is alkyl which is unsubstituted or substitutedwith R³⁶; R³⁶ is phenyl which is unfused or fused with arene,heteroarene or R^(36A); R^(36A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R³⁷ is R³⁸, R³⁹ or R⁴⁰, each ofwhich is substituted with F, Cl, Br, I, R⁴¹, OR⁴¹, NHR⁴¹, N(R⁴¹)₂,NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹; R³⁸ is phenyl which is unfused orfused with arene, heteroarene or R^(38A); R^(38A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R³⁹ is heteroarylwhich is unfused or fused with arene, heteroarene or R^(39A); R^(39A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R⁴⁰ isC₃-C₈-cycloalkyl or C₄-C₈-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(40A); R^(40A) cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁴¹ is R⁴², R⁴³, R⁴⁴ or R⁴⁵; R⁴²is phenyl which is unfused or fused with arene, heteroarene or R^(42A);R^(42A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R⁴³ is heteroaryl which is unfused or fused witharene, heteroarene or R^(43A); R^(43A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁴⁴ is C₃-C₉-cycloalkyl orC₄-C₇-cycloalkenyl, each having one or two CH₂ moieties unreplaced orreplaced with independently selected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂or NH and one or two CH moieties unreplaced or replaced with N, and eachof which is unfused or fused with arene, heteroarene or R^(44A); R^(44A)is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R⁴⁵is alkyl, alkenyl or alkynyl, each of which is unsubstituted orsubstituted with one or two independently selected R⁴⁶, OR⁴⁶, NHR⁴⁶,N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶, C(O)N(R⁴⁶)₂, OH, (O), C(O)OH, N₃, CN, NH₂,CF₃, CF₂CF₃, F, Cl, Br or I substituents; R⁴⁶ is R⁴⁷, R⁴⁸ or R⁴⁹; R⁴⁷ isphenyl which is unfused or fused with arene, heteroarene or R^(47A);R^(47A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R⁴⁸ is heteroaryl or R^(48A); R^(48A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R⁴⁹ isC₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(49A); R^(49A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; wherein the moieties representedby R²⁶ and R²⁷ are further substituted by one or two or three ofindependently selected R^(50A), OR^(50A), SR^(50A), S(O)R^(50A),SO₂R^(50A) or NHR^(50A), R^(50A) is R^(51A), R^(52A), R^(53A) orR^(54A); R^(51A) is phenyl which is unfused or fused with benzene,heteroarene or R^(51AA), wherein R^(51AA) is cycloalkane, cycloalkene orheterocycloalkane heterocycloalkene, R^(52A) is heteroaryl; R^(53A) isC₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl; each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(53AA); wherein R^(53AA) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R^(54A) is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoor three of independently selected R^(55AA), OR^(55AA), SR^(55AA),S(O)R^(55AA), SO₂R^(55AA), NHR^(55AA), N(R^(55AA))₂, C(O)R^(55AA),C(O)NH₂, C(O)NHR^(55AA), NHC(O)R^(55AA), NHSO₂R^(55AA), NHC(O)OR^(55AA),SO₂NH₂, SO₂NHR^(55AA), SO₂N(R^(55AA))₂, NHC(O)NH₂, NHC(O)NHR^(55AA), OH,(O), C(O)OH, (O), N₃, CN, NH₂, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, F, Cl, Br orI substituents; R^(55AA) is alkyl, alkenyl, alkynyl, phenyl orheteroaryl, or R^(56A); R^(56A) is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkyl,each having one or two CH₂ moieties unreplaced or replaced withindependently selected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and oneor two CH moieties unreplaced or replaced with N; wherein moietiesrepresented by R² R³ R⁴, R⁶, R^(6C), R⁸, R^(8A) R⁹, R¹⁰, R¹³, R¹⁴, R¹⁵,R¹⁸, R¹⁹, R²⁰, R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³⁴, R³⁶, R³⁸,R³⁹, R⁴⁰, R⁴², R⁴³, R⁴⁴, R⁴⁷, R⁴⁸, and R⁴⁹ are independentlyunsubstituted, further unsubstituted, substituted or further substitutedwith one or two or three or four or five independently selected R⁵⁰,OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰, CO(O)R⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰,NH₂, NHR⁵⁰, N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰, C(O)N(R⁵⁰)₂, C(O)NHOH,C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰, C(O)NR⁵⁵SO₂R⁵⁰, SO₂NH₂, SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂,CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰, C(N)N(R⁵⁰)₂, OH, (O),CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴; R⁵¹ is phenyl which is unfused or fusedwith arene, heteroarene or R^(51B); R^(51B) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁵² is heteroaryl; R⁵³ isC₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(53B); wherein R^(53B) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁵⁴ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoor three independently selected R⁵⁵, OR⁵⁵, SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, NHR⁵⁵,N(R⁵⁵)₂, C(O)R⁵⁵, C(O)NH₂, C(O)NHR⁵⁵, NHC(O)R⁵⁵, NHSO₂R⁵⁵, NHC(O)OR⁵⁵,SO₂NH₂, SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂, NHC(O)NH₂, NHC(O)NHR⁵⁵, OH, (O), C(O)OH,(O), N₃, CN, NH₂, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, F, Cl, Br or Isubstituents; R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R⁵⁶;wherein the alkyl, alkenyl, alkynyl are unsubstituted or substitutedwith OCH₃; and R⁵⁶ is C₃-C₈-cycloalkyl or C₄-C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N.
 2. A compound having formula II

or a therapeutically acceptable salt, prodrug or salt of prodrugthereof, wherein R¹⁰⁰ is as described for substituents on R²⁶; n is 0,1, 2, or 3; A¹ is N or C(A²); one or two or three or each of A², B¹, D¹and E¹ are independently selected R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹,C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹,NHC(O)OR¹, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NHR¹, SO₂N(R)₂, NHSO₂R¹,NHSO₂NHR¹ or N(CH₃)SO₂N(CH₃)R¹, and the remainder are independentlyselected H, F, Cl, Br, I, CN, CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); andY¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂,C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷; or B¹ and Y¹, togetherwith the atoms to which they are attached, are imidazole or triazole;and one or two or each of A², D¹ and E¹ are independently selected R¹,OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NHC(O)NHR¹,N(CH₃)C(O)N(CH₃)R¹, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ orN(CH₃)SO₂N(CH₃)R¹, and the remainder are independently selected H, F,Cl, Br, I, CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); R¹ is R², R³, R⁴ or R⁵;R^(1A) is C₁-C₆-alkyl, C₃-C₆-alkenyl or C₃-C₆-alkynyl; R² is phenylwhich is unfused or fused with arene, heteroarene or R^(2A); R^(2A) iscycloalkane or heterocycloalkane; R³ is heteroaryl which is unfused orfused with benzene, heteroarene or R^(3A); R^(3A) is cycloalkane orheterocycloalkane; R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl, each of which is unfused or fused with arene,heteroarene or R^(4A); R^(4A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁵ is alkyl, alkenyl or alkynyl,each of which is unsubstituted or substituted with one or two or threeindependently selected R⁶, NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷,SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷, C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷, NHSO₂R⁷,NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O),C(O)OH, (O), N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents; R⁶is C₂-C₅-spiroalkyl, each of which is unsubstituted or substituted withOH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) or N(CH₃)₂;R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C); R^(6C) is aziridin-1-yl,azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl, each having one CH₂moiety unreplaced or replaced with O, C(O), CNOH, CNOCH₃, S, S(O), SO₂or NH; R⁷ is R⁸, R⁹, R¹⁰ or R¹¹; R⁸ is phenyl which is unfused or fusedwith arene, heteroarene or R^(8A); R^(8A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁹ is heteroaryl which isunfused or fused with arene, heteroarene or R^(9A); R^(9A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁰ isC₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(10A); R^(10A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R¹¹ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoor three independently selected R¹², OR¹², NHR¹², N(R¹²)₂, C(O)NH₂,C(O)NHR¹², C(O)N(R¹²)₂, OH, (O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F,Cl, Br or I substituents; R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶; R¹³ is phenylwhich is unfused or fused with arene, heteroarene or R^(13A); R^(13A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁴ isheteroaryl, each of which is unfused or fused with arene, heteroarene orR^(14A); R^(14A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene, each of which is unfused or fused with arene,heteroarene or R^(15A); R^(15A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R¹⁶ is alkyl, alkenyl oralkynyl; R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹; R¹⁸ is phenyl which is unfused orfused with arene, heteroarene or R^(18A); R^(18A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁹ is heteroarylwhich is unfused or fused with arene, heteroarene or R^(19A); R^(19A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R²⁰ isC₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(20A); R^(20A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R²¹ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoor three independently selected R²², OR²², NHR²², N(R²²)₂, C(O)NH₂,C(O)NHR²², C(O)N(R²²)₂, OH, (O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F,Cl, Br or I substituents; R²² is R²³, R²⁴ or R²⁵; R²³ is phenyl which isunfused or fused with arene, heteroarene or R^(23A); R^(23A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R²⁴ isheteroarene which is unfused or fused with arene, heteroarene orR^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R²⁵ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N, and each of which is unfused orfused with arene, heteroarene or R^(25A); R^(25A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R³⁰ is cycloalkylor cycloalkenyl, each having one or two CH₂ moieties unreplaced orreplaced with independently selected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂or NH and one or two CH moieties unreplaced or replaced with N, and eachof which is unfused or fused with arene, heteroarene or R^(30A); R^(30A)is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;each of which is substituted with F, Cl, Br, I, CH₂R³⁷, CH(R³¹)(R³⁷),C(R³¹)(R^(31A))(R³⁷), C(O)R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, NHR³⁷ orN(R³²)R³⁷; R³¹ and R^(31A) are independently F, Cl, Br or alkyl or aretaken together and are C₂-C₅-spiroalkyl; R³² is R³³, C(O)R³³ orC(O)OR³³; R³³ is R³⁴ or R³⁵; R³⁴ is phenyl which is unfused or fusedwith aryl, heteroaryl or R^(34A); R^(34A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R³⁵ is alkyl which isunsubstituted or substituted with R³⁶; R³⁶ is phenyl which is unfused orfused with arene, heteroarene or R^(36A); R^(36A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R³⁷ is R³⁸, R³⁹ orR⁴⁰, each of which is substituted with F, Cl, Br, I, R⁴¹, OR⁴¹, NHR⁴¹,N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹; R³⁸ is phenyl which isunfused or fused with arene, heteroarene or R^(38A); R^(38A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R³⁹ isheteroaryl which is unfused or fused with arene, heteroarene or R^(39A);R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R⁴⁰ is C₃-C₈-cycloalkyl or C₄-C₈-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N, and each of which is unfused orfused with arene, heteroarene or R^(40A); R^(40A) cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R⁴¹ is R⁴², R⁴³,R⁴⁴ or R⁴⁵; R⁴² is phenyl which is unfused or fused with arene,heteroarene or R^(42A); R^(42A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁴³ is heteroaryl which isunfused or fused with arene, heteroarene or R^(43A); R^(43A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R⁴⁴ isC₃-C₉-cycloalkyl or C₄-C₇-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁴⁵ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoindependently selected R⁴⁶, OR⁴⁶, NHR⁴⁶, N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶,C(O)N(R⁴⁶)₂, OH, (O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or Isubstituents; R⁴⁶ is R⁴⁷, R⁴⁸ or R⁴⁹; R⁴⁷ is phenyl which is unfused orfused with arene, heteroarene or R^(47A); R^(47A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R⁴⁸ is heteroarylor R^(48A); R^(48A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R⁴⁹ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N, and each of which is unfused orfused with arene, heteroarene or R^(49A); R^(49A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; wherein moietiesrepresented by R² R³ R⁴, R⁶, R^(6C), R⁸, R^(8A) R⁹, R¹⁰, R¹³, R¹⁴, R¹⁵,R¹⁸, R¹⁹, R²⁰, R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³⁴, R³⁶, R³⁸,R³⁹, R⁴⁰, R⁴², R⁴³, R⁴⁴, R⁴⁷, R⁴⁸, and R⁴⁹ are independentlyunsubstituted, further unsubstituted, substituted or further substitutedwith one or two or three or four or five independently selected R⁵⁰,OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰, CO(O)R⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰,NH₂, NHR⁵⁰, N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰, C(O)N(R⁵⁰)₂, C(O)NHOH,C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰, C(O)NR⁵⁵SO₂R⁵⁰, SO₂NH₂, SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂,CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰, C(N)N(R⁵⁰)₂, OH, (O),CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴; R⁵¹ is phenyl which is unfused or fusedwith arene, heteroarene or R^(51B); R^(51B) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁵² is heteroaryl; R⁵³ isC₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(53B); wherein R^(53B) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁵⁴ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoor three independently selected R⁵⁵, OR⁵⁵, SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, NHR⁵⁵,N(R⁵⁵)₂, C(O)R⁵⁵, C(O)NH₂, C(O)NHR⁵⁵, NHC(O)R⁵⁵, NHSO₂R⁵⁵, NHC(O)OR⁵⁵,SO₂NH₂, SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂, NHC(O)NH₂, NHC(O)NHR⁵⁵, OH, (O), C(O)OH,(O), N₃, CN, NH₂, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, F, Cl, Br or Isubstituents; R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R⁵⁶;wherein the alkyl, alkenyl, alkynyl are unsubstituted or substitutedwith OCH₃; and R⁵⁶ is C₃-C₈-cycloalkyl or C₄-C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N.
 3. A compound having formula III

or a therapeutically acceptable salt, prodrug or salt of prodrugthereof, wherein R¹⁰⁰ is as described for substituents on R²⁶; n is 0,1, 2, or 3; A¹ is N or C(A²); one or two or three or each of A², B¹, D¹and E¹ are independently selected R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹,C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹,NHC(O)OR¹, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NHR¹, SO₂N(R)₂, NHSO₂R¹,NHSO₂NHR¹ or N(CH₃)SO₂N(CH₃)R¹, and the remainder are independentlyselected H, F, Cl, Br, I, CN, CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); andY¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂,C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷; or B¹ and Y¹, togetherwith the atoms to which they are attached, are imidazole or triazole;and one or two or each of A², D¹ and E¹ are independently selected R¹,OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NHC(O)NHR¹,N(CH₃)C(O)N(CH₃)R¹, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ orN(CH₃)SO₂N(CH₃)R¹, and the remainder are independently selected H, F,Cl, Br, I, CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); R¹ is R², R³, R⁴ or R⁵;R^(1A) is C₁-C₆-alkyl, C₃-C₆-alkenyl or C₃-C₆-alkynyl; R² is phenylwhich is unfused or fused with arene, heteroarene or R^(2A); R^(2A) iscycloalkane or heterocycloalkane; R³ is heteroaryl which is unfused orfused with benzene, heteroarene or R^(3A); R^(3A) is cycloalkane orheterocycloalkane; R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl, each of which is unfused or fused with arene,heteroarene or R^(4A); R^(4A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁵ is alkyl, alkenyl or alkynyl,each of which is unsubstituted or substituted with one or two or threeindependently selected R⁶, NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷,SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷, C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷, NHSO₂R⁷,NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O),C(O)OH, (O), N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents; R⁶is C₂-C₅-spiroalkyl, each of which is unsubstituted or substituted withOH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) or N(CH₃)₂;R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C); R^(6C) is aziridin-1-yl,azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl, each having one CH₂moiety unreplaced or replaced with O, C(O), CNOH, CNOCH₃, S, S(O), SO₂or NH; R⁷ is R⁸, R⁹, R¹⁰ or R¹¹; R⁸ is phenyl which is unfused or fusedwith arene, heteroarene or R^(8A); R^(8A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁹ is heteroaryl which isunfused or fused with arene, heteroarene or R^(9A); R^(9A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁰ isC₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(10A); R^(10A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R¹¹ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoor three independently selected R¹², OR¹², NHR¹², N(R¹²)₂, C(O)NH₂,C(O)NHR¹², C(O)N(R¹²)₂, OH, (O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F,Cl, Br or I substituents; R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶; R¹³ is phenylwhich is unfused or fused with arene, heteroarene or R^(13A); R^(13A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁴ isheteroaryl, each of which is unfused or fused with arene, heteroarene orR^(14A); R^(14A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene, each of which is unfused or fused with arene,heteroarene or R^(15A); R^(15A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R¹⁶ is alkyl, alkenyl oralkynyl; R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹; R¹⁸ is phenyl which is unfused orfused with arene, heteroarene or R^(18A); R^(18A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁹ is heteroarylwhich is unfused or fused with arene, heteroarene or R^(19A); R^(19A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R²⁰ isC₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(20A); R^(20A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R²¹ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoor three independently selected R²², OR²², NHR²², N(R²²)₂, C(O)NH₂,C(O)NHR²², C(O)N(R²²)₂, OH, (O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F,Cl, Br or I substituents; R²² is R²³, R²⁴ or R²⁵; R²³ is phenyl which isunfused or fused with arene, heteroarene or R^(23A); R^(23A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R²⁴ isheteroarene which is unfused or fused with arene, heteroarene orR^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R²⁵ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N, and each of which is unfused orfused with arene, heteroarene or R^(25A); R^(25A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R³⁰ is cycloalkylor cycloalkenyl, each having one or two CH₂ moieties unreplaced orreplaced with independently selected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂or NH and one or two CH moieties unreplaced or replaced with N, and eachof which is unfused or fused with arene, heteroarene or R^(30A); R^(30A)is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;each of which is substituted with F, Cl, Br, I, CH₂R³⁷, CH(R³¹)(R³⁷),C(R³¹)(R^(31A))(R³⁷), C(O)R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, NHR³⁷ orN(R³²)R³⁷; R³¹ and R^(31A) are independently F, Cl, Br or alkyl or aretaken together and are C₂-C₅-spiroalkyl; R³² is R³³, C(O)R³³ orC(O)OR³³; R³³ is R³⁴ or R³⁵; R³⁴ is phenyl which is unfused or fusedwith aryl, heteroaryl or R^(34A); R^(34A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R³⁵ is alkyl which isunsubstituted or substituted with R³⁶; R³⁶ is phenyl which is unfused orfused with arene, heteroarene or R^(36A); R^(36A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R³⁷ is R³⁸, R³⁹ orR⁴⁰, each of which is substituted with F, Cl, Br, I, R⁴¹, OR⁴¹, NHR⁴¹,N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹; R³⁸ is phenyl which isunfused or fused with arene, heteroarene or R^(38A); R^(38A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R³⁹ isheteroaryl which is unfused or fused with arene, heteroarene or R^(39A);R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R⁴⁰ is C₃-C₈-cycloalkyl or C₄-C₈-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N, and each of which is unfused orfused with arene, heteroarene or R^(40A); R^(40A) cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R⁴¹ is R⁴², R⁴³,R⁴⁴ or R⁴⁵; R⁴² is phenyl which is unfused or fused with arene,heteroarene or R^(42A); R^(42A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁴³ is heteroaryl which isunfused or fused with arene, heteroarene or R^(43A); R^(43A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R⁴⁴ isC₃-C₉-cycloalkyl or C₄-C₇-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁴⁵ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoindependently selected R⁴⁶, OR⁴⁶, NHR⁴⁶, N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶,C(O)N(R⁴⁶)₂, OH, (O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or Isubstituents; R⁴⁶ is R⁴⁷, R⁴⁸ or R⁴⁹; R⁴⁷ is phenyl which is unfused orfused with arene, heteroarene or R^(47A); R^(47A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R⁴⁸ is heteroarylor R^(48A); R^(48A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R⁴⁹ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N, and each of which is unfused orfused with arene, heteroarene or R^(49A); R^(49A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; wherein moietiesrepresented by R² R³ R⁴, R⁶, R^(6C), R⁸, R^(8A) R⁹, R¹⁰, R¹³, R¹⁴, R¹⁵,R¹⁸, R¹⁹, R²⁰, R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³⁴, R³⁶, R³⁸,R³⁹, R⁴⁰, R⁴², R⁴³, R⁴⁴, R⁴⁷, R⁴⁸, and R⁴⁹ are independentlyunsubstituted, further unsubstituted, substituted or further substitutedwith one or two or three or four or five independently selected R⁵⁰,OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰, CO(O)R⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰,NH₂, NHR⁵⁰, N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰, C(O)N(R⁵⁰)₂, C(O)NHOH,C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰, C(O)NR⁵⁵SO₂R⁵⁰, SO₂NH₂, SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂,CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰, C(N)N(R⁵⁰)₂, OH, (O),CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴; R⁵¹ is phenyl which is unfused or fusedwith arene, heteroarene or R^(51B); R^(51B) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁵² is heteroaryl; R⁵³ isC₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(53B); wherein R^(53B) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁵⁴ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoor three independently selected R⁵⁵, OR⁵⁵, SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, NHR⁵⁵,N(R⁵⁵)₂, C(O)R⁵⁵, C(O)NH₂, C(O)NHR⁵⁵, NHC(O)R⁵⁵, NHSO₂R⁵⁵, NHC(O)OR⁵⁵,SO₂NH₂, SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂, NHC(O)NH₂, NHC(O)NHR⁵⁵, OH, (O), C(O)OH,(O), N₃, CN, NH₂, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, F, Cl, Br or Isubstituents; R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R⁵⁶;wherein the alkyl, alkenyl, alkynyl are unsubstituted or substitutedwith OCH₃; and R⁵⁶ is C₃-C₈-cycloalkyl or C₄-C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N.
 4. A compound having formula IV

or a therapeutically acceptable salt, prodrug or salt of prodrugthereof, wherein R¹⁰⁰ is as described for substituents on R²⁶; n is 0,1, 2, or 3; A¹ is N or C(A²); one or two or three or each of A², B¹, D¹and E¹ are independently selected R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹,C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹,NHC(O)OR¹, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹,NHSO₂NHR¹ or N(CH₃)SO₂N(CH₃)R¹, and the remainder are independentlyselected H, F, Cl, Br, I, CN, CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); andY¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂,C(O)NHR¹⁷, C(O)N(R¹⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷; or B¹ and Y¹, togetherwith the atoms to which they are attached, are imidazole or triazole;and one or two or each of A², D¹ and E¹ are independently selected R¹,OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NHC(O)NHR¹,N(CH₃)C(O)N(CH₃)R¹, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ orN(CH₃)SO₂N(CH₃)R¹, and the remainder are independently selected H, F,Cl, Br, I, CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); R¹ is R², R³, R⁴ or R⁵;R^(1A) is C₁-C₆-alkyl, C₃-C₆-alkenyl or C₃-C₆-alkynyl; R² is phenylwhich is unfused or fused with arene, heteroarene or R^(2A); R^(2A) iscycloalkane or heterocycloalkane; R³ is heteroaryl which is unfused orfused with benzene, heteroarene or R^(3A); R^(3A) is cycloalkane orheterocycloalkane; R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl, each of which is unfused or fused with arene,heteroarene or R^(4A); R^(4A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁵ is alkyl, alkenyl or alkynyl,each of which is unsubstituted or substituted with one or two or threeindependently selected R⁶, NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷,SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷, C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷, NHSO₂R⁷,NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O),C(O)OH, (O), N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents; R⁶is C₂-C₅-spiroalkyl, each of which is unsubstituted or substituted withOH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) or N(CH₃)₂;R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C); R^(6C) is aziridin-1-yl,azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl, each having one CH₂moiety unreplaced or replaced with O, C(O), CNOH, CNOCH₃, S, S(O), SO₂or NH; R⁷ is R⁸, R⁹, R¹⁰ or R¹¹; R⁸ is phenyl which is unfused or fusedwith arene, heteroarene or R^(8A); R^(8A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁹ is heteroaryl which isunfused or fused with arene, heteroarene or R^(9A); R^(9A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁰ isC₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(10A); R^(10A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R¹¹ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoor three independently selected R¹², OR¹², NHR¹², N(R¹²)₂, C(O)NH₂,C(O)NHR¹², C(O)N(R¹²)₂, OH, (O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F,Cl, Br or I substituents; R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶; R¹³ is phenylwhich is unfused or fused with arene, heteroarene or R^(13A); R^(13A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁴ isheteroaryl, each of which is unfused or fused with arene, heteroarene orR^(14A); R^(14A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene, each of which is unfused or fused with arene,heteroarene or R^(15A); R^(15A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R¹⁶ is alkyl, alkenyl oralkynyl; R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹; R¹⁸ is phenyl which is unfused orfused with arene, heteroarene or R^(18A); R^(18A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁹ is heteroarylwhich is unfused or fused with arene, heteroarene or R^(19A); R^(19A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R²⁰ isC₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(20A); R^(20A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R²¹ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoor three independently selected R²², OR²², NHR²², N(R²²)₂, C(O)NH₂,C(O)NHR²², C(O)N(R²²)₂, OH, (O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F,Cl, Br or I substituents; R²² is R²³, R²⁴ or R²⁵; R²³ is phenyl which isunfused or fused with arene, heteroarene or R^(23A); R^(23A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R²⁴ isheteroarene which is unfused or fused with arene, heteroarene orR^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R²⁵ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N, and each of which is unfused orfused with arene, heteroarene or R^(25A); R^(25A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R³⁰ is cycloalkylor cycloalkenyl, each having one or two CH₂ moieties unreplaced orreplaced with independently selected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂or NH and one or two CH moieties unreplaced or replaced with N, and eachof which is unfused or fused with arene, heteroarene or R^(30A); R^(30A)is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;each of which is substituted with F, Cl, Br, I, CH₂R³⁷, CH(R³¹)(R³⁷),C(R³¹)(R^(31A))(R³⁷), C(O)R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, NHR³⁷ orN(R³²)R³⁷; R³¹ and R^(31A) are independently F, Cl, Br or alkyl or aretaken together and are C₂-C₅-spiroalkyl; R³² is R³³, C(O)R³³ orC(O)OR³³; R³³ is R³⁴ or R³⁵; R³⁴ is phenyl which is unfused or fusedwith aryl, heteroaryl or R^(34A); R^(34A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R³⁵ is alkyl which isunsubstituted or substituted with R³⁶; R³⁶ is phenyl which is unfused orfused with arene, heteroarene or R^(36A); R^(36A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R³⁷ is R³⁸, R³⁹ orR⁴⁰, each of which is substituted with F, Cl, Br, I, R⁴¹, OR⁴¹, NHR⁴¹,N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹; R³⁸ is phenyl which isunfused or fused with arene, heteroarene or R^(38A); R^(38A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R³⁹ isheteroaryl which is unfused or fused with arene, heteroarene or R^(39A);R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R⁴⁰ is C₃-C₈-cycloalkyl or C₄-C₈-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N, and each of which is unfused orfused with arene, heteroarene or R^(40A); R^(40A) cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R⁴¹ is R⁴², R⁴³,R⁴⁴ or R⁴⁵; R⁴² is phenyl which is unfused or fused with arene,heteroarene or R^(42A); R^(42A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁴³ is heteroaryl which isunfused or fused with arene, heteroarene or R^(43A); R^(43A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R⁴⁴ isC₃-C₉-cycloalkyl or C₄-C₇-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁴⁵ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoindependently selected R⁴⁶, OR⁴⁶, NHR⁴⁶, N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶,C(O)N(R⁴⁶)₂, OH, (O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or Isubstituents; R⁴⁶ is R⁴⁷, R⁴⁸ or R⁴⁹; R⁴⁷ is phenyl which is unfused orfused with arene, heteroarene or R^(47A); R^(47A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R⁴⁸ is heteroarylor R^(48A); R^(48A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R⁴⁹ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N, and each of which is unfused orfused with arene, heteroarene or R^(49A); R^(49A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; wherein moietiesrepresented by R² R³ R⁴, R⁶, R^(6C), R⁸, R^(8A) R⁹, R¹⁰, R¹³, R¹⁴, R¹⁵,R¹⁸, R¹⁹, R²⁰, R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³⁴, R³⁶, R³⁸,R³⁹, R⁴⁰, R⁴², R⁴³, R⁴⁴, R⁴⁷, R⁴⁸, and R⁴⁹ are independentlyunsubstituted, further unsubstituted, substituted or further substitutedwith one or two or three or four or five independently selected R⁵⁰,OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰, CO(O)R⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰,NH₂, NHR⁵⁰, N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰, C(O)N(R⁵⁰)₂, C(O)NHOH,C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰, C(O)NR⁵⁵SO₂R⁵⁰, SO₂NH₂, SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂,CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰, C(N)N(R⁵⁰)₂, OH, (O),CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴; R⁵¹ is phenyl which is unfused or fusedwith arene, heteroarene or R^(51B); R^(51B) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁵² is heteroaryl; R⁵³ isC₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(53B); wherein R^(53B) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁵⁴ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoor three independently selected R⁵⁵, OR⁵⁵, SR⁵⁵, S(O)R⁵, SO₂R⁵, NHR⁵⁵,N(R⁵⁵)₂, C(O)R⁵, C(O)NH₂, C(O)NHR⁵, NHC(O)R⁵, NHSO₂R⁵, NHC(O)OR⁵⁵,SO₂NH₂, SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂, NHC(O)NH₂, NHC(O)NHR⁵⁵, OH, (O), C(O)OH,(O), N₃, CN, NH₂, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, F, Cl, Br or Isubstituents; R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R⁵⁶;wherein the alkyl, alkenyl, alkynyl are unsubstituted or substitutedwith OCH₃; and R⁵⁶ is C₃-C₈-cycloalkyl or C₄-C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N.
 5. A compound having formula V

or a therapeutically acceptable salt, prodrug or salt of prodrugthereof, wherein R¹⁰⁰ is as described for substituents on R²⁶; n is 0,1, 2, or 3; A¹ is N or C(A²); one or two or three or each of A², B¹, D¹and E¹ are independently selected R¹, OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹,C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂, C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹,NHC(O)OR¹, NR¹C(O)NHR¹, NR¹C(O)N(R¹)₂, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹,NHSO₂NHR¹ or N(CH₃)SO₂N(CH₃)R¹, and the remainder are independentlyselected H, F, Cl, Br, I, CN, CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); andY¹ is H, CN, NO₂, C(O)OH, F, Cl, Br, I, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, R¹⁷,OR¹⁷, C(O)R¹⁷, C(O)OR¹⁷, SR¹⁷, NH₂, NHR¹⁷, N(R¹⁷)₂, NHC(O)R¹⁷, C(O)NH₂,C(O)NHR¹⁷, C(O)N(R⁷)₂, NHS(O)R¹⁷ or NHSO₂R¹⁷; or B¹ and Y¹, togetherwith the atoms to which they are attached, are imidazole or triazole;and one or two or each of A², D¹ and E¹ are independently selected R¹,OR¹, SR¹, S(O)R¹, SO₂R¹, C(O)R¹, C(O)OR¹, OC(O)R¹, NHR¹, N(R¹)₂,C(O)NHR¹, C(O)N(R¹)₂, NHC(O)R¹, NHC(O)OR¹, NHC(O)NHR¹,N(CH₃)C(O)N(CH₃)R¹, SO₂NHR¹, SO₂N(R¹)₂, NHSO₂R¹, NHSO₂NHR¹ orN(CH₃)SO₂N(CH₃)R¹, and the remainder are independently selected H, F,Cl, Br, I, CF₃, C(O)OH, C(O)NH₂ or C(O)OR^(1A); R¹ is R², R³, R⁴ or R⁵;R^(1A) is C₁-C₆-alkyl, C₃-C₆-alkenyl or C₃-C₆-alkynyl; R² is phenylwhich is unfused or fused with arene, heteroarene or R^(2A); R^(2A) iscycloalkane or heterocycloalkane; R³ is heteroaryl which is unfused orfused with benzene, heteroarene or R^(3A); R^(3A) is cycloalkane orheterocycloalkane; R⁴ is cycloalkyl, cycloalkenyl, heterocycloalkyl orheterocycloalkenyl, each of which is unfused or fused with arene,heteroarene or R^(4A); R^(4A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁵ is alkyl, alkenyl or alkynyl,each of which is unsubstituted or substituted with one or two or threeindependently selected R⁶, NC(R^(6A))(R^(6B)), R⁷, OR⁷, SR⁷, S(O)R⁷,SO₂R⁷, NHR⁷, N(R⁷)₂, C(O)R⁷, C(O)NH₂, C(O)NHR⁷, NHC(O)R⁷, NHSO₂R⁷,NHC(O)OR⁷, SO₂NH₂, SO₂NHR⁷, SO₂N(R⁷)₂, NHC(O)NH₂, NHC(O)NHR⁷,NHC(O)CH(CH₃)NHC(O)CH(CH₃)NH₂, NHC(O)CH(CH₃)NHC(O)CH(CH₃)NHR¹, OH, (O),C(O)OH, (O), N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or I substituents; R⁶is C₂-C₅-spiroalkyl, each of which is unsubstituted or substituted withOH, (O), N₃, CN, CF₃, CF₂CF₃, F, Cl, Br, I, NH₂, NH(CH₃) or N(CH₃)₂;R^(6A) and R^(6B) are independently selected alkyl or, together with theN to which they are attached, R^(6C); R^(6C) is aziridin-1-yl,azetidin-1-yl, pyrrolidin-1-yl or piperidin-1-yl, each having one CH₂moiety unreplaced or replaced with O, C(O), CNOH, CNOCH₃, S, S(O), SO₂or NH; R⁷ is R⁸, R⁹, R¹⁰ or R¹¹; R⁸ is phenyl which is unfused or fusedwith arene, heteroarene or R^(8A); R^(8A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁹ is heteroaryl which isunfused or fused with arene, heteroarene or R^(9A); R^(9A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁰ isC₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(10A); R^(10A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R¹¹ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoor three independently selected R¹², OR¹², NHR¹², N(R¹²)₂, C(O)NH₂,C(O)NHR¹², C(O)N(R¹²)₂, OH, (O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F,Cl, Br or I substituents; R¹² is R¹³, R¹⁴, R¹⁵ or R¹⁶; R¹³ is phenylwhich is unfused or fused with arene, heteroarene or R^(13A); R^(13A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁴ isheteroaryl, each of which is unfused or fused with arene, heteroarene orR^(14A); R^(14A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R¹⁵ is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene, each of which is unfused or fused with arene,heteroarene or R^(15A); R^(15A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R¹⁶ is alkyl, alkenyl oralkynyl; R¹⁷ is R¹⁸, R¹⁹, R²⁰ or R²¹; R¹⁸ is phenyl which is unfused orfused with arene, heteroarene or R^(18A); R^(18A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R¹⁹ is heteroarylwhich is unfused or fused with arene, heteroarene or R^(19A); R^(19A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R²⁰ isC₃-C₁₀-cycloalkyl or C₄-C₁₀-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(20A); R^(20A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R²¹ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoor three independently selected R²², OR²², NHR²², N(R²²)₂, C(O)NH₂,C(O)NHR²², C(O)N(R²²)₂, OH, (O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F,Cl, Br or I substituents; R²² is R²³, R²⁴ or R²⁵; R²³ is phenyl which isunfused or fused with arene, heteroarene or R^(23A); R^(23A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R²⁴ isheteroarene which is unfused or fused with arene, heteroarene orR^(24A); R^(24A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R²⁵ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N, and each of which is unfused orfused with arene, heteroarene or R^(25A); R^(25A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R³⁰ is cycloalkylor cycloalkenyl, each having one or two CH₂ moieties unreplaced orreplaced with independently selected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂or NH and one or two CH moieties unreplaced or replaced with N, and eachof which is unfused or fused with arene, heteroarene or R^(30A); R^(30A)is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene;each of which is substituted with F, Cl, Br, I, CH₂R³⁷, CH(R³¹)(R³⁷),C(R³¹)(R^(31A))(R³⁷), C(O)R³⁷, OR³⁷, SR³⁷, S(O)R³⁷, SO₂R³⁷, NHR³⁷ orN(R³²)R³⁷; R³¹ and R^(31A) are independently F, Cl, Br or alkyl or aretaken together and are C₂-C₅-spiroalkyl; R³² is R³³, C(O)R³³ orC(O)OR³³; R³³ is R³⁴ or R³⁵; R³⁴ is phenyl which is unfused or fusedwith aryl, heteroaryl or R^(34A); R^(34A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R³⁵ is alkyl which isunsubstituted or substituted with R³⁶; R³⁶ is phenyl which is unfused orfused with arene, heteroarene or R^(36A); R^(36A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R³⁷ is R³⁸, R³⁹ orR⁴⁰, each of which is substituted with F, Cl, Br, I, R⁴¹, OR⁴¹, NHR⁴¹,N(R⁴¹)₂, NHC(O)OR⁴¹, SR⁴¹, S(O)R⁴¹ or SO₂R⁴¹; R³⁸ is phenyl which isunfused or fused with arene, heteroarene or R^(38A); R^(38A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R³⁹ isheteroaryl which is unfused or fused with arene, heteroarene or R^(39A);R^(39A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R⁴⁰ is C₃-C₈-cycloalkyl or C₄-C₈-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N, and each of which is unfused orfused with arene, heteroarene or R^(40A); R^(40A) cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R⁴¹ is R⁴², R⁴³,R⁴⁴ or R⁴⁵; R⁴² is phenyl which is unfused or fused with arene,heteroarene or R^(42A); R^(42A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁴³ is heteroaryl which isunfused or fused with arene, heteroarene or R^(43A); R^(43A) iscycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R⁴⁴ isC₃-C₉-cycloalkyl or C₄-C₇-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(44A); R^(44A) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁴⁵ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoindependently selected R⁴⁶, OR⁴⁶, NHR⁴⁶, N(R⁴⁶)₂, C(O)NH₂, C(O)NHR⁴⁶,C(O)N(R⁴⁶)₂, OH, (O), C(O)OH, N₃, CN, NH₂, CF₃, CF₂CF₃, F, Cl, Br or Isubstituents; R⁴⁶ is R⁴⁷, R⁴⁸ or R⁴⁹; R⁴⁷ is phenyl which is unfused orfused with arene, heteroarene or R^(47A); R^(47A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; R⁴⁸ is heteroarylor R^(48A); R^(48A) is cycloalkane, cycloalkene, heterocycloalkane orheterocycloalkene; R⁴⁹ is C₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N, and each of which is unfused orfused with arene, heteroarene or R^(49A); R^(49A) is cycloalkane,cycloalkene, heterocycloalkane or heterocycloalkene; wherein moietiesrepresented by R² R³ R⁴, R⁶, R^(6C), R⁸, R^(8A) R⁹, R¹⁰, R¹³, R¹⁴, R¹⁵,R¹⁸, R¹⁹, R²⁰, R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰, R³⁴, R³⁶, R³⁸,R³⁹, R⁴⁰, R⁴², R⁴³, R⁴⁴, R⁴⁷, R⁴⁸, and R⁴⁹ are independentlyunsubstituted, further unsubstituted, substituted or further substitutedwith one or two or three or four or five independently selected R⁵⁰,OR⁵⁰, SR⁵⁰, S(O)R⁵⁰, SO₂R⁵⁰, C(O)R⁵⁰, CO(O)R⁵⁰, OC(O)R⁵⁰, OC(O)OR⁵⁰,NH₂, NHR⁵⁰, N(R⁵⁰)₂, C(O)NH₂, C(O)NHR⁵⁰, C(O)N(R⁵⁰)₂, C(O)NHOH,C(O)NHOR⁵⁰, C(O)NHSO₂R⁵⁰, C(O)NR⁵⁵SO₂R⁵⁰, SO₂NH₂, SO₂NHR⁵⁰, SO₂N(R⁵⁰)₂,CF₃, CF₂CF₃, C(O)H, C(O)OH, C(N)NH₂, C(N)NHR⁵⁰, C(N)N(R⁵⁰)₂, OH, (O),CN, N₃, NO₂, CF₃, CF₂CF₃, OCF₃, OCF₂CF₃, F, Cl, Br or I substituents;R⁵⁰ is R⁵¹, R⁵², R⁵³ or R⁵⁴; R⁵¹ is phenyl which is unfused or fusedwith arene, heteroarene or R^(51B); R^(51B) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁵² is heteroaryl; R⁵³ isC₃-C₆-cycloalkyl or C₄-C₆-cycloalkenyl, each having one or two CH₂moieties unreplaced or replaced with independently selected O, C(O),CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CH moieties unreplacedor replaced with N, and each of which is unfused or fused with arene,heteroarene or R^(53B); wherein R^(53B) is cycloalkane, cycloalkene,heterocycloalkane or heterocycloalkene; R⁵⁴ is alkyl, alkenyl oralkynyl, each of which is unsubstituted or substituted with one or twoor three independently selected R⁵⁵, OR⁵⁵, SR⁵⁵, S(O)R⁵⁵, SO₂R⁵⁵, NHR⁵⁵,N(R⁵⁵)₂, C(O)R⁵⁵, C(O)NH₂, C(O)NHR⁵⁵, NHC(O)R⁵⁵, NHSO₂R⁵⁵, NHC(O)OR⁵⁵,SO₂NH₂, SO₂NHR⁵⁵, SO₂N(R⁵⁵)₂, NHC(O)NH₂, NHC(O)NHR⁵⁵, OH, (O), C(O)OH,(O), N₃, CN, NH₂, CF₃, OCF₃, CF₂CF₃, OCF₂CF₃, F, Cl, Br or Isubstituents; R⁵⁵ is alkyl, alkenyl, alkynyl, phenyl, heteroaryl or R⁵⁶;wherein the alkyl, alkenyl, alkynyl are unsubstituted or substitutedwith OCH₃; and R⁵⁶ is C₃-C₈-cycloalkyl or C₄-C₆-cycloalkenyl, eachhaving one or two CH₂ moieties unreplaced or replaced with independentlyselected O, C(O), CNOH, CNOCH₃, S, S(O), SO₂ or NH and one or two CHmoieties unreplaced or replaced with N.
 6. The compound of claim 1,claim 2, claim 3, claim 4, or claim 5, wherein A¹ is C(A²); and A² is H.7. The compound of claim 1, claim 2, claim 3, claim 4, or claim 5,wherein A¹ is C(A²); A² is H; and B¹ is NHR¹.
 8. The compound of claim1, claim 2, claim 3, claim 4, or claim 5, wherein A¹ is C(A²); A² is H;B¹ is NHR¹; and D¹ is H.
 9. The compound of claim 1, claim 2, claim 3,claim 4, or claim 5, wherein A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H;and E¹ is H.
 10. The compound of claim 1, claim 2, claim 3, claim 4, orclaim 5, wherein A¹ is C(A²); A² is H; B¹ is NHR¹; D¹ is H; E¹ is H; andY¹ is NO₂.
 11. A compound of claim 1, wherein the compound is chosenfrom:4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;2-(benzyloxy)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(2-phenylethoxy)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenylthio)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(phenylthio)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(phenylthio)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenylsulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenylsulfinyl)benzamide;2-benzyl-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;2-benzyl-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;2-benzyl-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(2-phenylethyl)benzamide;2-(benzylamino)-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;2-anilino-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;2-anilino-4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-methoxy-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indazol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indazol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(1,2,3,4-tetrahydroquinolin-6-yloxy)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-(1,2,3,4-tetrahydroquinolin-6-yloxy)benzamide;4-(4-((4′-chloro-4-(pyrrolidin-1-ylmethyl)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-4-(2-pyrrolidin-1-ylethyl)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-cyclopentylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)-3-isobutylpiperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(2,4-dioxo-3-azabicyclo(3.2.0)hept-3-yl)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(3,3-dimethyl-2-oxoazetidin-1-yl)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(4-nitro-2H-1,2,3-triazol-2-yl)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((2-(2-piperidin-1-ylethoxy)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-((((1-ethylpyrrolidin-2-yl)methyl)amino)carbonyl)-4-methoxyphenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1-naphthyloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-naphthyloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-naphthyloxy)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2-naphthyloxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(quinolin-7-yloxy)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(quinolin-6-yloxy)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(isoquinolin-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(isoquinolin-5-yloxy)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(quinolin-6-yloxy)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-4-yloxy)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-6-yloxy)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(isoquinolin-7-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(isoquinolin-7-yloxy)benzamide;4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-4-yloxy)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-4-yloxy)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-methoxyphenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-methylphenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;N-((3-((chloro(difluoro)methyl)sulfonyl)-4-((3-(dimethylamino)propyl)amino)phenyl)sulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;2-(1H-indol-4-yloxy)-4-(4-((2-(4-methoxyphenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4,4-dimethyl-2-(4-(trifluoromethyl)phenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4,4-dimethyl-2-(4-(trifluoromethoxy)phenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4,4-dimethyl-2-(3-(trifluoromethyl)phenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;4-(4-((2-(3-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;4-(4-((2-(4-fluorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;N-((3-((chloro(difluoro)methyl)sulfonyl)-4-((1-methylpiperidin-4-yl)amino)phenyl)sulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(phenoxymethyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(pyridin-3-yloxy)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(pyridin-3-yloxy)-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(((1R)-3-(dimethylamino)-1-((phenylthio)methyl)propyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(pyridin-4-yloxy)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(pyridin-3-yloxy)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-(pyridin-4-yloxy)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(4-methylpiperazin-1-yl)propyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)(methyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-cyano-4-((3-(dimethylamino)propyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-(trifluoromethyl)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(isopropyl(methyl)amino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(3-(dimethylamino)propoxy)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((3-(4-methylpiperazin-1-yl)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((3-(4-methylpiperazin-1-yl)propyl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(3-(dimethylamino)propoxy)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((2-(4-methylpiperazin-1-yl)ethyl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-(((1-methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(3-(dimethylamino)propoxy)-3-nitrophenyl)sulfonyl)-2-(1H-indol-4-yloxy)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-(4-methylpiperazin-1-yl)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)phenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-(((4-(dimethylamino)-1-methylpiperidin-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydro-1,4-benzodioxin-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-1,1′-biphenyl-2-carboxamide;5-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-1,1′-biphenyl-2-carboxamide;4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-4-(3-piperidin-1-ylpropoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-4-(3-(dimethylamino)propoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-4-(3-piperidin-1-ylpropoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-4-(3-(dimethylamino)propoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-3-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-3-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-3-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-4-(2-morpholin-4-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-4-(2-(dimethylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((1-(2,2,2-trifluoroethyl)piperidin-4-yl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-4-(2-pyrrolidin-1-ylethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-4-(2-(diisopropylamino)ethoxy)-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-(2,3-dihydro-1H-indol-5-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)cyclooct-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)cyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((3-pyrrolidin-1-ylpropyl)amino)phenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)cyclooct-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)cyclopent-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)cyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)cyclohept-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((1-methylpiperidin-4-yl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((2-(dimethylamino)ethyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-morpholin-4-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((4-(dimethylamino)butyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((1-(phenylsulfonyl)piperidin-4-yl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((1-(quinolin-8-ylsulfonyl)piperidin-4-yl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((1-(phenylsulfonyl)piperidin-4-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((1-(quinolin-8-ylsulfonyl)piperidin-4-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-(((1S)-3-(dimethylamino)-1-thien-2-ylpropyl)amino)-3-nitrophenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((thien-2-ylmethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-2-phenoxy-N-((4-((tetrahydro-2H-pyran-4-ylmethyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((2-(1H-1,2,3-triazol-1-yl)ethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((2-(2H-1,2,3-triazol-2-yl)ethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-nitrophenyl)sulfonyl)-2-(2-naphthyloxy)benzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((2-(2-oxopyridin-1(2H)-yl)ethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((2-(pyridin-2-yloxy)ethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((4′-chloro-1,1′-biphenyl-2-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((2-pyridin-4-ylethyl)amino)phenyl)sulfonyl)-2-phenoxybenzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((4-((3-(dimethylamino)propyl)amino)-3-(trifluoromethyl)phenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-cyano-4-((3-(dimethylamino)propyl)amino)phenyl)sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((3-nitro-4-((1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino)phenyl)sulfonyl)benzamide;4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-((4-((4-methylpiperazin-1-yl)amino)-3-nitrophenyl)sulfonyl)benzamide;4-(4-(1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)benzamide;N-((4-(((4-aminotetrahydro-2H-pyran-4-yl)methyl)amino)-3-nitrophenyl)sulfonyl)-4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3S)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(3R)-tetrahydro-2H-pyran-3-ylmethyl]amino}phenyl)sulfonyl]benzamide;4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-3-fluoro-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-3-fluoro-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxy-1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;N-[(4-{[(3S,4R)-1-benzyl-3-hydroxypiperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2-hydroxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[1-(2-methoxyethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;4-[4-({4′-chloro-3-[3-(dimethylamino)propyl]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(3-hydroxypropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;4-{4-[(4′-chloro-4-morpholin-4-yl-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(dimethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(diethylamino)cyclohexyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-[4-({4′-chloro-3-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(dimethylamino)tetrahydro-2H-pyran-4-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;N-({4-[(2-aminocyclohexyl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;4-[4-({4′-chloro-4-[3-(dimethylamino)prop-1-ynyl]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[1-(4,4,4-trifluorobutyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[2-(4-hydroxy-1-methylpiperidin-4-yl)ethyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-2-yl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;4-(4-{[4′-chloro-4-(2-hydroxyethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(cyclopropylmethyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(4,4,4-trifluorobutyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;4-(4-{[4′-chloro-4-(2-hydroxyethoxy)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[3-(3-oxopiperazin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(2,3-dihydro-1H-inden-2-yl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1-morpholin-4-ylcyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-2-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[1-(1,3-thiazol-4-ylmethyl)piperidin-4-yl]amino}phenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(2-hydroxyethyl)piperazin-1-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(3S)-1-methylpyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[1-(3-fluoropropyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;N-[(4-{[(4-aminotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-[4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}-3-(hydroxymethyl)piperazin-1-yl]-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[4-(hydroxymethyl)tetrahydro-2H-pyran-4-yl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-hydroxy-1-tetrahydro-2H-pyran-4-ylethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-({1-[2-(1H-pyrazol-1-yl)ethyl]piperidin-4-yl}amino)phenyl]sulfonyl}benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(methylamino)-3-nitrophenyl]sulfonyl}benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(methylamino)-3-nitrophenyl]sulfonyl}benzamide;4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-5-hydroxycyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-5-morpholin-4-ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;N-[(4-{[(1-aminocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxopyrrolidin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide;4-{4-[1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-{4-[(1R)-1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-{4-[(1S)-1-(4′-chloro-1,1′-biphenyl-2-yl)ethyl]piperazin-1-yl}-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{1-[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]ethyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(cyclohexylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-3-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(morpholin-4-ylamino)-3-nitrophenyl]sulfonyl}benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylamino)phenyl]sulfonyl}benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(3-methyloxetan-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methoxycyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(1,1-dioxidothiomorpholin-4-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxopiperidin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(2-oxoimidazolidin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2-pyridin-4-ylethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-morpholin-4-yl-3-nitrophenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(4-methoxypiperidin-1-yl)-3-nitrophenyl]sulfonyl}benzamide;4-(4-{[2-(4-chlorophenyl)-5-pyrrolidin-1-ylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(3-oxopiperazin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide;4-[4-({4′-chloro-4-[2-(dimethylamino)ethoxy]-1,1′-biphenyl-2-yl}methyl)piperazin-1-yl]-2-(1H-indol-4-yloxy)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1,1-dioxidotetrahydrothien-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-(trifluoromethyl)phenyl]sulfonyl}benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[2-(1,3-dioxolan-2-yl)ethyl]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[2-(3-oxopiperazin-1-yl)ethyl]amino}phenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methyl-5-oxopyrrolidin-3-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methyl-6-oxopiperidin-3-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(piperidin-1-ylamino)phenyl]sulfonyl}benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(piperidin-1-ylamino)phenyl]sulfonyl}benzamide;4-(4-{[4-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methyloxetan-3-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(1-oxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}phenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1,3-thiazol-5-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide;4-(4-{[2-(4-chlorophenyl)-5,5-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2-tetrahydro-2H-pyran-4-ylethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(3-nitro-4-{[2-(trifluoromethoxy)ethyl]amino}phenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]amino}-3-nitrophenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[3-(methylsulfonyl)propyl]amino}-3-nitrophenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(1,1-dioxidothiomorpholin-4-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethyl)phenyl]sulfonyl}benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]amino}-3-nitrophenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidotetrahydrothien-3-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[2-(trifluoromethoxy)ethyl]amino}phenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2,2-difluoroethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4,4-difluorocyclohexyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;4-(4-{[4-(4-chlorophenyl)-1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}phenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-hydroxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[3-nitro-4-(2-tetrahydro-2H-pyran-4-ylethoxy)phenyl]sulfonyl}benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-methoxyethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[3-(methylsulfonyl)propoxy]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-methoxypropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-methoxypropyl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2-cyanoethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(3R)-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[Cis-4-hydroxy-1-adamantyl]methyl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(3,3,3-trifluoropropyl)amino]phenyl}sulfonyl)benzamide;N-({5-bromo-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1,1-dioxidotetrahydrothien-3-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-(methylamino)-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;N-{[5-bromo-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[4-(4-chlorophenyl)-6-isopropoxypyridin-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[6-(tetrahydro-2H-pyran-4-ylmethoxy)-5-(1,3-thiazol-2-yl)pyridin-3-yl]sulfonyl}benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(2-methoxyethyl)amino]carbonyl}phenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;N-({4-[(1-acetylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[1-(methylsulfonyl)piperidin-4-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;4-(4-{[4′-chloro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[4′-chloro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide;4-{4-[(5-tert-butyl-4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-{4-[(5-tert-butyl-4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-{[3-nitro-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(2,2,2-trifluoroethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]carbonyl}phenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2R)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2S)-1,4-dioxan-2-ylmethoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;N-({5-bromo-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(2-morpholin-4-ylethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]pyridin-3-yl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)oxy]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(1-methylpiperidin-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[4-(4-chlorophenyl)-1-(3-hydroxypropyl)-1,2,5,6-tetrahydropyridin-3-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;benzyl4-({[4-({[4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzoyl]amino}sulfonyl)-2-nitrophenyl]amino}methyl)piperidine-1-carboxylate;N-{[3-(aminocarbonyl)-4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[4′-chloro-5-(trifluoromethyl)-1,1′-biphenyl-2-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;4-{4-[(5-tert-butyl-4′-chloro-1,1′-biphenyl-2-yl)methyl]piperazin-1-yl}-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1-methyl-1H-imidazol-5-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(morpholin-4-ylsulfonyl)phenyl]sulfonyl}benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,1-dioxidothiomorpholin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;N-{[5-bromo-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[6-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-5-(1,3-thiazol-2-yl)pyridin-3-yl]sulfonyl}benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-cyano-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3,3-dimethylbutyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1S)-1-(hydroxymethyl)-3-methylbutyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}phenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1R)-1-(hydroxymethyl)-2-methylpropyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-methoxyphenyl)amino]-3-nitrophenyl}sulfonyl)benzamide;N-[(4-{[2-(1,3-benzodioxol-5-yl)ethyl]amino}-3-nitrophenyl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}phenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-hydroxyphenyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;N-{[4-({2-[4-(aminosulfonyl)phenyl]ethyl}amino)-3-nitrophenyl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[3-(1H-imidazol-1-yl)propyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(3-nitro-4-{[(1S)-1-phenylethyl]amino}phenyl)sulfonyl]benzamide;N-({2-chloro-5-fluoro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]thio}-3-nitrophenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-[(4-{[2-(2-methoxyethoxy)ethyl]thio}-3-nitrophenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-{[4-(methylsulfonyl)phenyl]sulfonyl}benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)-N-{[4-(methylsulfonyl)phenyl]sulfonyl}benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)oxy]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-({4-[(4-morpholin-4-ylbut-2-ynyl)oxy]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-ethynyl-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-morpholin-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(3-hydroxy-4-methoxyphenyl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indol-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(2,3-dihydro-1H-indol-4-yloxy)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(pyridin-3-ylamino)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(pyridin-3-ylamino)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)-2-(pyridin-3-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1,2,3,4-tetrahydroisoquinolin-5-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-cyano-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-3-nitrophenyl}sulfonyl)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-indazol-4-yloxy)benzamide;N-[(5-chloro-6-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;Trans-N-({5-chloro-6-[(4-methoxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(2,2-difluoroethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(1-tetrahydro-2H-pyran-4-ylpiperidin-4-yl)amino]phenyl}sulfonyl)benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-methylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;N-[(5-chloro-6-{[1-(cyanomethyl)-4-fluoropiperidin-4-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydrofuran-3-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;Trans-N-({5-chloro-6-[(4-hydroxycyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;2-(1H-benzimidazol-4-yloxy)-N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;N-[(5-chloro-6-{[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;N-[(5-chloro-6-{[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(cyanomethyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-(2-methoxyethoxy)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(3R)-1-(N,N-dimethylglycyl)pyrrolidin-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(cyanomethyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyclopropylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(3-nitro-4-{[(4-oxetan-3-ylmorpholin-2-yl)methyl]amino}phenyl)sulfonyl]benzamide;N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}oxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}amino)-3-nitrophenyl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)-2-(1H-indazol-4-yloxy)benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2R)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[(2S)-4-(N,N-dimethylglycyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydrofuran-3-ylmethyl)amino]phenyl}sulfonyl)benzamide;Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-fluorotetrahydro-2H-pyran-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({5-fluoro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)benzamide;2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;N-{[5-chloro-6-({(3R)-1-[2-fluoro-1-(fluoromethyl)ethyl]pyrrolidin-3-yl}methoxy)pyridin-3-yl]sulfonyl}-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;N-[(5-chloro-6-{[(3R)-1-(2,2-difluoroethyl)pyrrolidin-3-yl]methoxy}pyridin-3-yl)sulfonyl]-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;Trans-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)-N-[(4-{[(4-methoxycyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-(1,4-dioxan-2-ylmethoxy)-3-nitrophenyl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(1-cyclopropylpiperidin-4-yl)amino]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1,4-dioxan-2-ylmethyl)amino]-3-nitrophenyl}sulfonyl)benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(1-cyclopropylpiperidin-4-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-morpholin-4-ylcyclohexyl)amino]-3-nitrophenyl}sulfonyl)benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[(4-methylpiperazin-1-yl)amino]-3-nitrophenyl}sulfonyl)benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(1-methylpiperidin-4-yl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({4-[({(2R)-4-[2-(2-methoxyethoxy)ethyl]morpholin-2-yl}methyl)amino]-3-nitrophenyl}sulfonyl)benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4,4-difluorocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;N-[(4-{[(4-acetylmorpholin-2-yl)methyl]amino}-3-nitrophenyl)sulfonyl]-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[4-({[4-(methylsulfonyl)morpholin-2-yl]methyl}amino)-3-nitrophenyl]sulfonyl}benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[6-({4-fluoro-1-[2-fluoro-1-(fluoromethyl)ethyl]piperidin-4-yl}methoxy)-5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-chloro-6-(2-tetrahydrofuran-2-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;Trans-2-(1H-benzimidazol-4-yloxy)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-[(4-{[(4-cyanocyclohexyl)methyl]amino}-3-nitrophenyl)sulfonyl]benzamide;2-(1H-benzimidazol-4-yloxy)-N-({5-chloro-6-[(4,4-difluorocyclohexyl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)benzamide;N-({3-chloro-4-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]phenyl}sulfonyl)-4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;N-({5-chloro-6-[(4-fluorotetrahydro-2H-pyran-4-yl)methoxy]pyridin-3-yl}sulfonyl)-4-(4-{[4-(4-chlorophenyl)-6,6-dimethyl-5,6-dihydro-2H-pyran-3-yl]methyl}piperazin-1-yl)-2-(1H-indazol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-{[5-cyano-6-(2-tetrahydro-2H-pyran-4-ylethoxy)pyridin-3-yl]sulfonyl}-2-(1H-indazol-4-yloxy)benzamide;4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-2-(1H-indol-5-yloxy)-N-[(4-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}-3-nitrophenyl)sulfonyl]benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxy-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxy-4-(4-{(3-phenylpropanoyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxy-4-(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxy-4-(4-{(3-phenylpropyl)[(1S,2S,3S,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}piperidin-1-yl)benzamide;4-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)piperazin-1-yl]-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide;4-[4-(2-{[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]amino}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]-3-[(trifluoromethyl)sulfonyl]phenyl}sulfonyl)benzamide;4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-2-phenoxy-N-({4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)benzamide;4-{4-[2-(3-azabicyclo[3.2.2]non-3-yl)benzyl]piperazin-1-yl}-N-({4-[(3-morpholin-4-ylpropyl)amino]-3-nitrophenyl}sulfonyl)-2-phenoxybenzamide;4-(4-{2-[(4R,7S)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoinden-5-yl]benzyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;4-[4-(2-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;4-[4-(2-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzylidene)piperidin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;4-[4-(3-{5-[(1R,5S)-8-azabicyclo[3.2.1]oct-8-ylmethyl]thien-2-yl}benzyl)piperazin-1-yl]-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-phenoxybenzamide;and therapeutically acceptable salts, prodrugs, salts of prodrugs andmetabolites thereof.
 12. A composition for treating bladder cancer,brain cancer, breast cancer, bone marrow cancer, cervical cancer,chronic lymphocytic leukemia, colorectal cancer, esophageal cancer,hepatocellular cancer, lymphoblastic leukemia, follicular lymphoma,lymphoid malignancies of T-cell or B-cell origin, melanoma, myelogenousleukemia, myeloma, oral cancer, ovarian cancer, non-small cell lungcancer, chronic lymphocytic leukemia, myeloma, prostate cancer, smallcell lung cancer or spleen cancer, said composition comprising anexcipient and a therapeutically effective amount of the compound ofclaim
 1. 13. A method of treating bladder cancer, brain cancer, breastcancer, bone marrow cancer, cervical cancer, chronic lymphocyticleukemia, colorectal cancer, esophageal cancer, hepatocellular cancer,lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies ofT-cell or B-cell origin, melanoma, myelogenous leukemia, myeloma, oralcancer, ovarian cancer, non-small cell lung cancer, chronic lymphocyticleukemia, myeloma, prostate cancer, small cell lung cancer or spleencancer in a patient, said method comprising administering to the patienta therapeutically effective amount of a compound of claim
 1. 14. Amethod of treating bladder cancer, brain cancer, breast cancer, bonemarrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectalcancer, esophageal cancer, hepatocellular cancer, lymphoblasticleukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cellorigin, melanoma, myelogenous leukemia, myeloma, oral cancer, ovariancancer, non-small cell lung cancer, chronic lymphocytic leukemia,myeloma, prostate cancer, small cell lung cancer or spleen cancer in apatient, said method comprising administering to the patienttherapeutically effective amount of the compound of claim 1 and atherapeutically effective amount of one additional therapeutic agent ormore than one additional therapeutic agent.